Chiral diaryl macrocycles as modulators of protein kinases

ABSTRACT

The present disclosure relates to certain chiral diaryl macrocyclic derivatives, pharmaceutical compositions containing them, and methods of using them to treat cancer, pain, neurological diseases, autoimmune diseases, and inflammation.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 62/188,043, filed on Jul. 2, 2015, and U.S.Provisional Patent Application Ser. No. 62/353,728, filed on Jun. 23,2016, the entire disclosures of which are incorporated herein byreference.

TECHNICAL FIELD

The present disclosure relates to certain chiral diaryl macrocyclicderivatives, pharmaceutical compositions containing them, and methods ofusing them to treat cancer, pain, neurological diseases, autoimmunediseases, and inflammation.

BACKGROUND

Protein kinases are key regulators for cell growth, proliferation andsurvival. Genetic and epigenetic alterations accumulate in cancer cellsleading to abnormal activation of signal transduction pathways whichdrive malignant processes. Manning, G. et al., Science 2002, 298,1912-1934. Pharmacological inhibition of these signaling pathwayspresents promising intervention opportunities for targeted cancertherapies. Sawyers, C., Nature 2004, 432, 294-297.

ALK, along with leukocyte tyrosine kinase (LTK), is grouped within theinsulin receptor (IR) superfamily of receptor tyrosine kinases. ALK ismainly expressed in the central and peripheral nervous systemssuggesting a potential role in normal development and function of thenervous system. Pulford, K. et al., Cell Mol. Life Sci. 2004, 61, 2939.ALK was first discovered as a fusion protein, NPM (nucleophosmin)-ALK,encoded by a fusion gene arising from the t(2;5)(p23;q35) chromosomaltranslocation in anaplastic large cell lymphoma (ALCL) cell lines.Morris, S. W. et al., Science 1994, 263, 1281. More than twenty distinctALK translocation partners have been discovered in many cancers,including ALCL (60-90% incidence), inflammatory myofibroblastic tumors(IMT, 50-60%), non-small cell lung carcinomas (NSCLC, 3-7%), colorectalcancers (CRC, 0-2.4%), breast cancers (0-2.4%), and other carcinomas.Grande, E. et al., Mol. Cancer Ther. 2011, 10, 569-579. The ALK-fusionproteins are located in the cytoplasm, and the fusion partners with ALKplay a role in dimerization or oligomerization of the fusion proteinsthrough a coil-coil interaction to generate constitutive activation ofALK kinase function. Bischof, D. et al., Mol. Cell Biol., 1997, 17,2312-2325. EML4-ALK, which comprises portions of the echinodermmicrotubule associated protein-like 4 (EML4) gene and the ALK gene, wasfirst discovered in NSCLC, is highly oncogenic, and was shown to causelung adenocarcinoma in transgenic mice. Soda, M. et al., Nature 2007,448, 561-566. Oncogenic point mutations of ALK in both familial andsporadic cases of neuroblastoma. Mossé, Y. P. et al., Nature 2008, 455,930-935. ALK is an attractive molecular target for cancer therapeuticintervention because of the important roles in haematopoietic, solid,and mesenchymal tumors. Grande, supra.

The tropomyosin-related receptor tyrosine kinases (Trks) are thehigh-affinity receptor for neurotrophins (NTs), a nerve growth factor(NGF) family of proteins. Members of the Trk family are highly expressedin cells of neural origin. Activation of Trks (TrkA, TrkB, and TrkC) bytheir preferred neurotrophins (NGF to TrkA, brain-derived neurotrophicfactor [BDNF] and NT4/5 to TrkB, and NT3 to TrkC) mediates the survivaland differentiation of neurons during development. The NT/Trk signalingpathway functions as an endogenous system that protects neurons afterbiochemical insults, transient ischemia, or physical injury. Thiele, C.J. et al., Clin. Cancer Res. 2009, 15, 5962-5967. However, Trk wasoriginally cloned as an oncogene fused with the tropomyosin gene in theextracellular domain. The activating mutations caused by chromosomalrearrangements or mutations in NTRK1 (TrkA) has been identified inpapillary and medullary thyroid carcinoma, and recently in non-smallcell lung cancer. Pierotti, M. A. et al., Cancer Lett. 2006, 232, 90-98;Vaishnavi, A. et al., Nat. Med. 2013, 19, 1469-1472. Because Trks playimportant roles in pain sensation as well as tumor cell growth andsurvival signaling, inhibitors of Trk receptor kinases may providebenefits as treatments for pain and cancer.

The Janus family of kinases (JAKs) includes JAK1, JAK2, JAK3 and TYK2,and are cytoplastic tyrosine kinases required for the physiologicsignaling of cytokines and growth factors. Quintas-Cardama, A. et al.,Nat. Rev. Drug Discov. 2011, 10(2), 127-40; Pesu, M. et al., Immunol.Rev. 2008, 223, 132-142; Murray, P. J., J. Immunol. 2007, 178(5),2623-2329. JAKs activate by ligand-induced oligomerization, resulting inthe activation of downstream transcriptional signaling pathway calledSTAT (signal transducers and activators of transcription). Thephosphorylated STATs dimerize and translocate into nucleus to drive theexpression of specific genes involved in proliferation, apoptosis,differentiation, which are essential for hematopoiesis, inflammation andimmune response. Murray, supra.

Mouse knockout studies have implicated the primary roles of JAK-STATsignaling with some overlap between them. JAK1 plays a critical role inthe signaling of various proinflammatory cytokines such as IL-1, IL-4,IL-6, and tumor necrosis factor alpha (TNFα). Muller, M. et al., Nature1993, 366(6451), 129-135. JAK2 functions for hematopoietic growthfactors signaling such as Epo, IL-3, IL-5, GM-CSF, thrombopoietin growthhormone, and prolactin-mediated signaling. Neubauer, H. et al., Cell1998 93(3), 397-409. JAK3 plays a role in mediating immune responses,and TYK2 associates with JAK2 or JAK3 to transduce signaling ofcytokines, such as IL-12. Nosaka, T. et al., Science 1995, 270(5237),800-802; Vainchenker, W. et al., Semin. Cell. Dev. Biol. 2008, 19(4),385-393.

Aberrant regulation of JAK/STAT pathways has been implicated in multiplehuman pathological diseases, including cancer (JAK2) and rheumatoidarthritis (JAK1, JAK3). A gain-of-function mutation of JAK2 (JAK2V617F)has been discovered with high frequency in MPN patients. Levine, R. L.et al., Cancer Cell 2005, 7(4), 387-397; Kralovics, R. et al., N. Engl.J. Med. 2005, 253(17), 1779-1790; James, C. et al., Nature 2005,434(7037), 1144-1148; Baxter, E. J. et al. Lancet 2005, 365(9464),1054-1061. The mutation in the JH2 pseudokinase domain of JAK2 leads toconstitutively kinase activity. Cells containing JAK2V617F mutantationacquire cytokine-independent growth ability and often become tumor,providing strong rational for the development of JAK inhibitors astarget therapy.

Multiple JAK inhibitors in clinical trial showed significant benefit insplenomegaly and disease related constitutional symptoms for themyelofibrosis patients, including the first FDA-approved JAK2 inhibitorruxolitinib in 2011. Quintas-Cardama, supra; Sonbol, M. B. et al., Ther.Adv. Hematol. 2013, 4(1), 15-35; LaFave, L. M. et al., Trends Pharmacol.Sci. 2012, 33(11), 574-582. The recently collected clinical data relatedto ruxolitinib treatment indicated that JAK inhibitors work on both JAK2wild-type and JAK2 mutated cases. Verstovsek, S. et al., N. Engl. J.Med. 2012, 366(9), 799-807; Quintas-Cardama, A. et al., Blood 2010,115(15), 3109-3117. The discovery of selective inhibitors of JAK2 vsJAK1/3 remains an unsolved challenge. In addition, hyperactivation ofthe JAK2/signal transducers and activators of transcription 3(JAK2/STAT3) is responsible for abnormal dendritic cell differentiationleading to abnormal dendritic cell differentiation and accumulation ofimmunosuppressive myeloid cells in cancer (Nefedova, Y. et al., CancerRes 2005; 65(20): 9525-35). In Pten-null senescent tumors, activation ofthe Jak2/Stat3 pathway establishes an immunosuppressive tumormicroenvironment that contributes to tumor growth and chemoresistance(Toso, A. et al., Cell Reports 2014, 9, 75-89). Therefore, pharmacologicinhibition of the JAK2/STAT3 pathway can be an important new therapeuticstrategy to enhance antitumor activity via the regulation of antitumorimmunity.

ROS1 kinase is a receptor tyrosine kinase with an unknown ligand. Thenormal functions of human ROS1 kinase have not been fully understood.However, it has been reported that ROS1 kinase undergoes geneticrearrangements to create constitutively active fusion proteins in avariety of human cancers including glioblastoma, non-small cell lungcancer (NSCLC), cholangiocarcinoma, ovarian cancer, gastricadenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor,angiosarcoma, and epithelioid hemangioendothelioma (Davies, K. D. etal., Clin Cancer Res 2013, 19 (15): 4040-4045). Targeting ROS1 fusionproteins with crizotinib has demonstrated promising clinical efficacy inNSCLC patients whose tumors are positive for ROS1 genetic abnormalities(Shaw, A. T. et al., N Engl J Med. 2014, 371(21):1963-1971). Acquiredresistant mutations have been observed in crizotinib treatment patients(Awad, M. M. et al., N Engl J Med. 2013, 368(25):2396-2401). It isurgent to develop the second generation of ROS1 inhibitors forovercoming crizotinib ROS1 resistance.

Crizotinib (PF-02341066) is a tyrosine kinase drug targetingMET/ALK/ROS1/RON with moderate activity against TRKs and AXL. Cui, J. J.et al., J. Med. Chem. 2011, 54, 6342-6363. It was approved to treatcertain patients with late-stage (locally advanced or metastatic) NSCLCthat expresses the abnormal ALK fusion gene identified by a companiondiagnostic test (Vysis ALK Break Apart FISH Probe Kit). Similar toimatinib and other kinase inhibitor drugs, resistance invariablydevelops after a certain time of treatment with crizotinib. Theresistance mechanisms include ALK gene amplification, secondary ALKmutations, and aberrant activation of other kinases including KIT andEGFR. Katayama, R. et al., Sci. Transl. Med. 2012, 4, 120ra17. Based onthe clinical success of second generation ABL inhibitors for thetreatment of imatinib resistance in CML patients, a second generation ofALK inhibitors is emerging. These drugs target the treatment ofcrizotinib-refractory or resistant NSCLC patient with more potentinhibition against both wild and mutant ALK proteins. Gridelli, C. etal., Cancer Treat Rev. 2014, 40, 300-306.

There remains a need for small molecule inhibitors of these multipleprotein or tyrosine kinase targets with desirable pharmaceuticalproperties. Certain chiral diaryl macrocyclic compounds have been foundin the context of this disclosure to have this advantageous activityprofile.

SUMMARY

In one aspect, the disclosure relates to a compound of the formula I

wherein

M is CR^(4a) or N;

M¹ is CR⁵ or N;

X¹ and X² are independently S, S(O), S(O)₂, O or N(R⁹);

R¹ is H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein each hydrogenatom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl andC₆-C₁₀ aryl is independently optionally substituted by deuterium,halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂,—NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂,—NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆alkyl), —NHS(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl), —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl),—NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl; or R² and R³ taken together with thecarbon atoms to which they are attached optionally form a C₅-C₇cycloalkyl or a 5- to 7-membered heterocycloalkyl; or R² and R⁶ takentogether with the atoms to which they are attached optionally form a 5-to 7-membered heterocycloalkyl;

R⁴, R^(4a) and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆alkyl, —OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or—CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or heteroaryl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—OC₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or —CF₃,

n is 1 or 2; and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;and provided that at least one R¹, R² or R³ is not H;

or a pharmaceutically acceptable salt thereof.

In one aspect, the disclosure relates to a compound of the formula I-1

wherein

M is CR^(4a) or N;

X¹ and X² are independently S, S(O), S(O)₂, O or N(R⁹);

R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl isindependently optionally substituted by deuterium, halogen, —OH, —CN,—OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆alkyl), —N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆alkyl), —NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

each of R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁

C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl),—S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂,—P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to7-membered heterocycloalkyl;

R⁴, R^(4a) and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆alkyl, —OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or—CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or heteroaryl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—OC₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or —CF₃, and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;

or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure relates to a compound of the formulaIa

wherein

M is CR^(4a) or N;

X¹ and X² are independently S, S(O), S(O)₂, O or N(R⁹);

R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl isindependently optionally substituted by deuterium, halogen, —OH, —CN,—OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆alkyl), —N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆alkyl), —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

each of R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

R⁴, R^(4a) and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆alkyl, —OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or—CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or heteroaryl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—OC₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or —CF₃, and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;

or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure relates to a compound of the formulaIb

wherein

M is CR^(4a) or N;

X¹ and X² are independently S, S(O), S(O)₂, O or N(R⁹);

R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl isindependently optionally substituted by deuterium, halogen, —OH, —CN,—OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆alkyl), —N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆alkyl), —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

each R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl; or R² and R³ taken together with thecarbon atoms to which they are attached optionally form a C₅-C₇cycloalkyl or a 5- to 7-membered heterocycloalkyl; or R² and R⁶ takentogether with the atoms to which they are attached optionally form a 5-to 7-membered heterocycloalkyl;

R⁴, R^(4a) and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆alkyl, —OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or—CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or heteroaryl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—OC₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or —CF₃,

n is 1 or 2; and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;

or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure relates to a compound of the formulaIc

wherein

M is CR^(4a) or N;

X¹ and X² are independently S, S(O), S(O)₂, O or N(R⁹);

each R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl; or R² and R³ taken together with thecarbon atoms to which they are attached optionally form a C₅-C₇cycloalkyl or a 5- to 7-membered heterocycloalkyl; or R² and R⁶ takentogether with the atoms to which they are attached optionally form a 5-to 7-membered heterocycloalkyl;

R⁴, R^(4a) and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆alkyl, —OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or—CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or heteroaryl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—O—C₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or —CF₃,

n is 1 or 2; and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;

or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure relates to a compound of the formulaII

wherein

M is CH or N;

X¹ and X² are independently S, S(O), S(O)₂, O or N(R⁹);

each of R¹ and R² is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl and C₆-C₁₀ aryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, —C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or heteroaryl; and

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure relates to a compound of the formulaIII

wherein

M is CH or N;

X¹ and X² are independently S, S(O), S(O)₂, O or N(R⁹);

each of R¹ and R² is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl and C₆-C₁₀ aryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or heteroaryl; and

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure relates to a compound of the formulaIV

wherein

M is CH or N;

X¹ and X² are independently S, S(O), S(O)₂, O or N(R⁹);

each of R¹ and R³ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl and C₆-C₁₀ aryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or heteroaryl; and

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure relates to a compound of the formula V

wherein

M is CH or N;

X¹ and X² are independently S, S(O), S(O)₂, O or N(R⁹);

each of R¹ and R³ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl and C₆-C₁₀ aryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or heteroaryl; and

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure relates to a compound of the formulaVI

wherein

M is CH or N;

X¹ and X² are independently S, S(O), S(O)₂, O or N(R⁹);

R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl isindependently optionally substituted by deuterium, halogen, —OH, —CN,—OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆alkyl), —N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆alkyl), —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or heteroaryl; and

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure relates to a compound selected fromthe group consisting of

wherein

M is CH or N;

X¹ and X² are independently S, S(O), S(O)₂, O or N(R⁹);

R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl isindependently optionally substituted by deuterium, halogen, —OH, —CN,—OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆alkyl), —N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆alkyl), —NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

R² and R³ taken together with the carbon atoms to which they areattached optionally form a C₅-C₇ cycloalkyl or a 5- to 7-memberedheterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or heteroaryl; and

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure relates to a compound selected fromthe group consisting of

wherein

M is CH or N;

X¹ and X² are independently S, S(O), S(O)₂, O or N(R⁹);

R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl isindependently optionally substituted by deuterium, halogen, —OH, —CN,—OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆alkyl), —N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆alkyl), —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

R² and R⁶ taken together with the atoms to which they are attachedoptionally form a 5- to 7-membered heterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or heteroaryl; and

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure relates to a pharmaceuticalcomposition comprising a compound of the Formula I, I-1, Ia, Ib, Ic, II,III, IV, V, VI, VII, VIII, IX, X, XI, XII or XIII, or a pharmaceuticallyacceptable salt thereof, and optionally at least one diluent, carrier orexcipient.

In another aspect, the disclosure is directed to a method of treatingcancer, pain, neurological diseases, autoimmune diseases, orinflammation comprising administering to a subject in need of suchtreatment an effective amount of at least one compound of Formula I,I-1, Ia, Ib, Ic, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII or XIII,or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure is directed to use of a compound ofFormula I, I-1, Ia, Ib, Ic, II, III, IV, V, VI, VII, VIII, IX, X, XI,XII or XIII, or a pharmaceutically acceptable salt thereof, in thepreparation of a medicament for the treatment of cancer, pain,neurological diseases, autoimmune diseases, or inflammation.

In another aspect, the disclosure is directed to use of a compound ofFormula I, I-1, Ia, Ib, Ic, II, III, IV, V, VI, VII, VIII, IX, X, XI,XII or XIII, or a pharmaceutically acceptable salt thereof, for treatingcancer, pain, neurological diseases, autoimmune diseases, orinflammation

In another aspect, the disclosure is directed to use of a compound ofFormula I, I-1, Ia, Ib, Ic, II, III, IV, V, VI, VII, VIII, IX, X, XI,XII or XIII, or a pharmaceutically acceptable salt thereof, in thepreparation of a medicament for the treatment of such diseases andmedical conditions, and the use of such compounds and salts fortreatment of such diseases and medical conditions.

In yet another aspect, the disclosure relates to a method of inhibitingprotein or tyrosine kinases, including one or more of MET, ALK, ROS1,AXL, TRKs, and JAKs, comprising contacting a cell comprising one or moreof such kinases with an effective amount of at least one compound ofFormula I, I-1, Ia, Ib, Ic, II, III, IV, V, VI, VII, VIII, IX, X, XI,XII or XIII, or a pharmaceutically acceptable salt thereof, and/or withat least one pharmaceutical composition of the disclosure, wherein thecontacting is in vitro, ex vivo, or in vivo.

Additional embodiments, features, and advantages of the disclosure willbe apparent from the following detailed description and through practiceof the disclosure. The compounds of the present disclosure can bedescribed as embodiments in any of the following enumerated clauses.

It will be understood that any of the embodiments described herein canbe used in connection with any other embodiments described herein to theextent that the embodiments do not contradict one another.

1. A compound of the formula I

wherein

M is CR⁴a or N;

M¹ is CR⁵ or N;

X¹ and X² are independently S, S(O), S(O)₂, O or N(R⁹);

R¹ is H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein each hydrogenatom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl andC₆-C₁₀ aryl is independently optionally substituted by deuterium,halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂,—NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂,—NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆alkyl), —NHS(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl), —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl),—NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl; or R² and R³ taken together with thecarbon atoms to which they are attached optionally form a C₅-C₇cycloalkyl or a 5- to 7-membered heterocycloalkyl; or R² and R⁶ takentogether with the atoms to which they are attached optionally form a 5-to 7-membered heterocycloalkyl;

R⁴, R^(4a) and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆alkyl, —OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or—CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or heteroaryl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—OC₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or —CF₃,

n is 1 or 2; and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;and provided that at least one R¹, R² or R³ is not H;

or a pharmaceutically acceptable salt thereof.

1a. A compound of the formula I-1

wherein

M is CR^(4a) or N;

X¹ and X² are independently S, S(O), S(O)₂, O or N(R⁹);

R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl isindependently optionally substituted by deuterium, halogen, —OH, —CN,—OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆alkyl), —N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆alkyl), —NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

each of R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

R⁴, R^(4a) and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆alkyl, —OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or—CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or heteroaryl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—OC₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or —CF₃, and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;

or a pharmaceutically acceptable salt thereof.

2. The compound of clause 1 or 1a, having the formula Ia

wherein

M is CR^(4a) or N;

X¹ and X² are independently S, S(O), S(O)₂, O or N(R⁹);

R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl isindependently optionally substituted by deuterium, halogen, —OH, —CN,—OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆alkyl), —N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆alkyl), —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

each of R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

R⁴, R^(4a) and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆alkyl, —OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or—CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or heteroaryl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—OC₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or —CF₃, and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;

or a pharmaceutically acceptable salt thereof.

2a. The compound of clause 1 or 1a, having the formula Ib

wherein

M is CR^(4a) or N;

X¹ and X² are independently S, S(O), S(O)₂, O or N(R⁹);

R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl isindependently optionally substituted by deuterium, halogen, —OH, —CN,—OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆alkyl), —N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆alkyl), —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

each R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl; or R² and R³ taken together with thecarbon atoms to which they are attached optionally form a C₅-C₇cycloalkyl or a 5- to 7-membered heterocycloalkyl; or R² and R⁶ takentogether with the atoms to which they are attached optionally form a 5-to 7-membered heterocycloalkyl;

R⁴, R^(4a) and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆alkyl, —OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or—CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or heteroaryl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—OC₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or —CF₃,

n is 1 or 2; and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;

or a pharmaceutically acceptable salt thereof.

2b. The compound of clause 1 or 1a, having the formula Ic

wherein

M is CR^(4a) or N;

X¹ and X² are independently S, S(O), S(O)₂, O or N(R⁹);

each R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl; or R² and R³ taken together with thecarbon atoms to which they are attached optionally form a C₅-C₇cycloalkyl or a 5- to 7-membered heterocycloalkyl; or R² and R⁶ takentogether with the atoms to which they are attached optionally form a 5-to 7-membered heterocycloalkyl;

R⁴, R^(4a) and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆alkyl, —OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or—CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or heteroaryl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—O—C₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or —CF₃,

n is 1 or 2; and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;

or a pharmaceutically acceptable salt thereof.

3. The compound of clause 1, 1a, 2, 2a or 2b, or a pharmaceuticallyacceptable salt thereof, wherein Z¹, Z⁴ and Z⁷ are N and Z², Z³, Z⁵ andZ⁶ are CH.

4. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein X¹ is N(R⁹).

5. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein R⁹ is H.

6. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein X² is O.

7. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein R² is C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂,

C₃-C₆ cycloalkyl, or 3- to 7-membered heterocycloalkyl, and R³ is H.

8. The compound of any one of clauses 1 to 6, or a pharmaceuticallyacceptable salt thereof, wherein R² is H, and R³ is C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl.

9. The compound of any one of clauses 1 to 6, or a pharmaceuticallyacceptable salt thereof, wherein R² and R³ are H.

10. The compound of any one of clauses 1 to 7, having the formula II

wherein

M is CH or N;

X¹ and X² are independently S, S(O), S(O)₂, O or N(R⁹);

each of R¹ and R² is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl and C₆-C₁₀ aryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, —C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or heteroaryl; and

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

or a pharmaceutically acceptable salt thereof.

11. The compound of any one of clauses 1 to 7, having the formula III

wherein

M is CH or N;

X¹ and X² are independently S, S(O), S(O)₂, O or N(R⁹);

each of R¹ and R² is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl and C₆-C₁₀ aryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or heteroaryl; and

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

or a pharmaceutically acceptable salt thereof.

12. The compound of any one of clauses 1 to 6 or 8, having the formulaIV

wherein

M is CH or N;

X¹ and X² are independently S, S(O), S(O)₂, O or N(R⁹);

each of R¹ and R³ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl and C₆-C₁₀ aryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or heteroaryl; and

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

or a pharmaceutically acceptable salt thereof.

13. The compound of any one of clauses 1 to 6 or 8, having the formula V

wherein

M is CH or N;

X¹ and X² are independently S, S(O), S(O)₂, O or N(R⁹);

each of R¹ and R³ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl and C₆-C₁₀ aryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or heteroaryl; and

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

or a pharmaceutically acceptable salt thereof.

14. The compound of any one of clauses 1 to 6 or 9, having the formulaVI

wherein

M is CH or N;

X¹ and X² are independently S, S(O), S(O)₂, O or N(R⁹);

R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl isindependently optionally substituted by deuterium, halogen, —OH, —CN,—OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆alkyl), —N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆alkyl), —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or heteroaryl; and

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

or a pharmaceutically acceptable salt thereof.

14a. The compound of any one of clauses 1, 1a, 2 or 2a having a formulaselected from the group consisting of

wherein

M is CH or N;

X¹ and X² are independently S, S(O), S(O)₂, O or N(R⁹);

R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl isindependently optionally substituted by deuterium, halogen, —OH, —CN,—OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆alkyl), —N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆alkyl), —NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

R² and R³ taken together with the carbon atoms to which they areattached optionally form a C₅-C₇ cycloalkyl or a 5- to 7-memberedheterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or heteroaryl; and

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

or a pharmaceutically acceptable salt thereof.

14b. The compound of any one of clauses 1, 1a, 2 or 2a having a formulaselected from the group consisting of

wherein

M is CH or N;

X¹ and X² are independently S, S(O), S(O)₂, or N(R⁹);

R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl isindependently optionally substituted by deuterium, halogen, —OH, —CN,—OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆alkyl), —N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆alkyl), —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

R² and R⁶ taken together with the atoms to which they are attachedoptionally form a 5- to 7-membered heterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or heteroaryl; and

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;

or a pharmaceutically acceptable salt thereof.

15. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein R⁵ is —H.

16. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein R⁴ is —F.

17. The compound of any one of clauses 1-7, 10, 11, 15 or 16, or apharmaceutically acceptable salt thereof, wherein R², when present, isC₁-C₆ alkyl and each hydrogen atom in C₁-C₆ alkyl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl or 3-to 7-membered heterocycloalkyl.

18. The compound of any one of clauses 1-7, 10, 11 or 15 to 17, or apharmaceutically acceptable salt thereof, wherein R², when present, isC₁-C₆ alkyl substituted with one or more moieties selected from groupconsisting of —F, —OH, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), and—N(C₁-C₆ alkyl)₂.

19. The compound of any one of clauses 1-7, 10, 11 or 15 to 18, or apharmaceutically acceptable salt thereof, wherein R², when present, ismethyl.

20. The compound of any one of clauses 1-7, 10, 11 or 15 to 18, or apharmaceutically acceptable salt thereof, wherein R², when present, isethyl.

21. The compound of any one of clauses 1-7, 10, 11 or 15 to 18, or apharmaceutically acceptable salt thereof, wherein R², when present, ishydroxymethyl.

22. The compound of any one of clauses 1-7, 10, 11 or 15 to 18, or apharmaceutically acceptable salt thereof, wherein R², when present, isfluoromethyl.

23. The compound of any one of clauses 1-7, 10, 11 or 15 to 18, or apharmaceutically acceptable salt thereof, wherein R², when present, ismethoxymethyl.

24. The compound of any one of clauses 1-7, 10, 11 or 15 to 18, or apharmaceutically acceptable salt thereof, wherein R², when present, isdifluoromethyl.

25. The compound of any one of clauses 1-7, 10, 11 or 15 to 18, or apharmaceutically acceptable salt thereof, wherein R², when present, istrifluoromethyl.

26. The compound of any one of clauses 1-7, 10, 11 or 15 to 18, or apharmaceutically acceptable salt thereof, wherein R², when present, isC₁-C₆ alkyl substituted with —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆alkyl)₂.

27. The compound of any one of clauses 1-7, 10, 11 or 15 to 18, or apharmaceutically acceptable salt thereof, wherein R², when present, ismethyl substituted with —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂.

28. The compound of any one of clauses 1-7, 10, 11 or 15 to 18, or apharmaceutically acceptable salt thereof, wherein R², when present, ismethyl substituted with —N(CH₃)₂.

29. The compound of any one of clauses 1-7, 10, 11, 15 or 16, or apharmaceutically acceptable salt thereof, wherein R², when present, is—C(O)NR⁷R⁸.

30. The compound of clause 29, or a pharmaceutically acceptable saltthereof, wherein R⁷ and R⁸ are H.

31. The compound of any one of clauses 1-6, 8, 12, 13, 15 or 16, or apharmaceutically acceptable salt thereof, wherein R³, when present, isC₁-C₆ alkyl and each hydrogen atom in C₁-C₆ alkyl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl or 3-to 7-membered heterocycloalkyl.

32. The compound of any one of clauses 1-6, 8, 12, 13, 15, 16 or 31, ora pharmaceutically acceptable salt thereof, wherein R³, when present, isC₁-C₆ alkyl substituted with one or more moieties selected from groupconsisting of —F, —OH, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), and—N(C₁-C₆ alkyl)₂.

33. The compound of any one of clauses 1-6, 8, 12, 13, 15, 16, 31 or 32,or a pharmaceutically acceptable salt thereof, wherein R³, when present,is methyl.

34. The compound of any one of clauses 1-6, 8, 12, 13, 15, 16, 31 or 32,or a pharmaceutically acceptable salt thereof, wherein R³, when present,is ethyl.

35. The compound of any one of clauses 1-6, 8, 12, 13, 15, 16, 31 or 32,or a pharmaceutically acceptable salt thereof, wherein R³, when present,is hydroxymethyl.

36. The compound of any one of clauses 1-6, 8, 12, 13, 15, 16, 31 or 32,or a pharmaceutically acceptable salt thereof, wherein R³, when present,is fluoromethyl.

37. The compound of any one of clauses 1-6, 8, 12, 13, 15, 16, 31 or 32,or a pharmaceutically acceptable salt thereof, wherein R³, when present,is methoxymethyl.

38. The compound of any one of clauses 1-6, 8, 12, 13, 15, 16, 31 or 32,or a pharmaceutically acceptable salt thereof, wherein R³, when present,is difluoromethyl.

39. The compound of any one of clauses 1-6, 8, 12, 13, 15, 16, 31 or 32,or a pharmaceutically acceptable salt thereof, wherein R³, when present,is trifluoromethyl.

40. The compound of any one of clauses 1-6, 8, 12, 13, 15, 16, 31 or 32,or a pharmaceutically acceptable salt thereof, wherein R³, when present,is C₁-C₆ alkyl substituted with —NH₂, —NH(C₁-C₆ alkyl) or —N(C₁-C₆alkyl)₂.

41. The compound of any one of clauses 1-6, 8, 12, 13, 15, 16, 31 or 32,or a pharmaceutically acceptable salt thereof, wherein R³, when present,is methyl substituted with —NH₂, —NH(C₁-C₆ alkyl) or —N(C₁-C₆ alkyl)₂.

42. The compound of any one of clauses 1-6, 8, 12, 13, 15, 16, 31 or 32,or a pharmaceutically acceptable salt thereof, wherein R³, when present,is methyl substituted with —N(CH₃)₂.

43. The compound of any one of clauses 1-6, 8, 12, 13, 15 or 16, or apharmaceutically acceptable salt thereof, wherein R³, when present, is—C(O)NR⁷R⁸.

44. The compound of clause 43, or a pharmaceutically acceptable saltthereof, wherein R⁷ and R⁸ are H.

45. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein R¹, when present, isC₁-C₆ alkyl and each hydrogen atom in C₁-C₆ alkyl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl or 3-to 7-membered heterocycloalkyl.

46. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein R¹, when present, isC₁-C₆ alkyl substituted with one or more —F or —OH.

47. The compound of any one of clauses 1 to 46, or a pharmaceuticallyacceptable salt thereof, wherein R¹, when present, is C₁-C₆ alkyl.

48. The compound of any one of clauses 1 to 46, or a pharmaceuticallyacceptable salt thereof, wherein R¹, when present, is methyl.

49. The compound of any one of clauses 1 to 46, or a pharmaceuticallyacceptable salt thereof, wherein R¹, when present, is ethyl.

50. The compound of any one of clauses 1 to 46, or a pharmaceuticallyacceptable salt thereof, wherein R¹, when present, is 2-hydroxy-ethyl.

51. The compound of any one of clauses 1 to 46, or a pharmaceuticallyacceptable salt thereof, wherein R¹, when present, is 2-fluoro-ethyl.

52. The compound of any one of clauses 1 to 46, or a pharmaceuticallyacceptable salt thereof, wherein R¹, when present, is2-hydroxy-2-propyl.

53. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein M is CR^(4a)

54. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein M is CR^(4a), andR^(4a) is H.

55. The compound of clause 1, of the formula selected from the groupconsisting of

or a pharmaceutically acceptable salt thereof.

56. The compound of clause 1, of the formula selected from the groupconsisting of

or a pharmaceutically acceptable salt thereof.

57. The compound of clause 1, of the formula selected from the groupconsisting of

or a pharmaceutically acceptable salt thereof.

58. The compound of clause 1, of the formula selected from the groupconsisting of

or a pharmaceutically acceptable salt thereof.

59. The compound of clause 1, of the formula selected from the groupconsisting of

or a pharmaceutically acceptable salt thereof.

60. The compound of clause 1, of the formula selected from the groupconsisting of

or a pharmaceutically acceptable salt thereof.

61. A pharmaceutical composition comprising a compound of any one of thepreceding clauses, or a pharmaceutically acceptable salt thereof, andoptionally at least one diluent, carrier or excipient.

62. A method of treating cancer, pain, neurological diseases, autoimmunediseases, or inflammation comprising administering to a subject in needof such treatment an effective amount of at least one compound of anyone of clauses 1 to 60, or a pharmaceutically acceptable salt thereof.

63. Use of a compound of any one of clauses 1 to 60, or apharmaceutically acceptable salt thereof, in the preparation of amedicament for the treatment of cancer, pain, neurological diseases,autoimmune diseases, or inflammation.

64. Use of a compound of any one of clauses 1 to 60, or apharmaceutically acceptable salt thereof, for treating cancer, pain,neurological diseases, autoimmune diseases, or inflammation.

65. A method of inhibiting protein or tyrosine kinases, including one ormore of MET, ALK, ROS1, AXL, TRKs, and JAKs, comprising contacting acell comprising one or more of such kinases with an effective amount ofat least one compound of any one of clauses 1 to 60, or apharmaceutically acceptable salt thereof, and/or with at least onepharmaceutical composition of the disclosure, wherein the contacting isin vitro, ex vivo, or in vivo.

66. A compound of any one of clauses 1 to 60 for use in treating cancerin a patient.

67. A compound of any one of clauses 1 to 60 for use in treatinginflammation in a patient.

DETAILED DESCRIPTION

Before the present disclosure is further described, it is to beunderstood that this disclosure is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present disclosure will be limited only by the appendedclaims.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this disclosure belongs. All patents, applications,published applications and other publications referred to herein areincorporated by reference in their entireties. If a definition set forthin this section is contrary to or otherwise inconsistent with adefinition set forth in a patent, application, or other publication thatis herein incorporated by reference, the definition set forth in thissection prevails over the definition incorporated herein by reference.

As used herein and in the appended claims, the singular forms “a,” “an,”and “the” include plural referents unless the context clearly dictatesotherwise. It is further noted that the claims may be drafted to excludeany optional element. As such, this statement is intended to serve asantecedent basis for use of such exclusive terminology as “solely,”“only” and the like in connection with the recitation of claim elements,or use of a “negative” limitation.

As used herein, the terms “including,” “containing,” and “comprising”are used in their open, non-limiting sense.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

Except as otherwise noted, the methods and techniques of the presentembodiments are generally performed according to conventional methodswell known in the art and as described in various general and morespecific references that are cited and discussed throughout the presentspecification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, NewYork: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith andMarch, March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, Fifth Edition, Wiley-Interscience, 2001.

Chemical nomenclature for compounds described herein has generally beenderived using the commercially-available ACD/Name 2014 (ACD/Labs) orChemBioDraw Ultra 13.0 (Perkin Elmer).

It is appreciated that certain features of the disclosure, which are,for clarity, described in the context of separate embodiments, may alsobe provided in combination in a single embodiment. Conversely, variousfeatures of the disclosure, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables arespecifically embraced by the present disclosure and are disclosed hereinjust as if each and every combination was individually and explicitlydisclosed, to the extent that such combinations embrace compounds thatare stable compounds (i.e., compounds that can be isolated,characterized, and tested for biological activity). In addition, allsubcombinations of the chemical groups listed in the embodimentsdescribing such variables are also specifically embraced by the presentdisclosure and are disclosed herein just as if each and every suchsub-combination of chemical groups was individually and explicitlydisclosed herein.

Definitions

As used herein, the term “alkyl” includes a chain of carbon atoms, whichis optionally branched and contains from 1 to 20 carbon atoms. It is tobe further understood that in certain embodiments, alkyl may beadvantageously of limited length, including C₁-C₁₂, C₁-C₁₀, C₁-C₉,C₁-C₈, C₁-C₇, C₁-C₆, and C₁-C₄, Illustratively, such particularlylimited length alkyl groups, including C₁-C₈, C₁-C₇, C₁-C₆, and C₁-C₄,and the like may be referred to as “lower alkyl.” Illustrative alkylgroups include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl,3-pentyl, neopentyl, hexyl, heptyl, octyl, and the like. Alkyl may besubstituted or unsubstituted. Typical substituent groups includecycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,mercapto, alkylthio, arylthio, cyano, halo, carbonyl, oxo, (═O),thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, C-carboxy, O-carboxy, nitro, and amino, or asdescribed in the various embodiments provided herein. It will beunderstood that “alkyl” may be combined with other groups, such as thoseprovided above, to form a functionalized alkyl. By way of example, thecombination of an “alkyl” group, as described herein, with a “carboxy”group may be referred to as a “carboxyalkyl” group. Other non-limitingexamples include hydroxyalkyl, aminoalkyl, and the like.

As used herein, the term “alkenyl” includes a chain of carbon atoms,which is optionally branched, and contains from 2 to 20 carbon atoms,and also includes at least one carbon-carbon double bond (i.e. C═C). Itwill be understood that in certain embodiments, alkenyl may beadvantageously of limited length, including C₂-C₁₂, C₂-C₉, C₂-C₅, C₂-C₇,C₂-C₆, and C₂-C₄. Illustratively, such particularly limited lengthalkenyl groups, including C₂-C₈, C₂-C₇, C₂-C₆, and C₂-C₄ may be referredto as lower alkenyl. Alkenyl may be unsubstituted, or substituted asdescribed for alkyl or as described in the various embodiments providedherein. Illustrative alkenyl groups include, but are not limited to,ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.

As used herein, the term “alkynyl” includes a chain of carbon atoms,which is optionally branched, and contains from 2 to 20 carbon atoms,and also includes at least one carbon-carbon triple bond (i.e. C≡C). Itwill be understood that in certain embodiments, alkynyl may each beadvantageously of limited length, including C₂-C₁₂, C₂-C₉, C₂-C₈, C₂-C₇,C₂-C₆, and C₂-C₄. Illustratively, such particularly limited lengthalkynyl groups, including C₂-C₈, C₂-C₇, C₂-C₆, and C₂-C₄ may be referredto as lower alkynyl. Alkenyl may be unsubstituted, or substituted asdescribed for alkyl or as described in the various embodiments providedherein. Illustrative alkenyl groups include, but are not limited to,ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.

As used herein, the term “aryl” refers to an all-carbon monocyclic orfused-ring polycyclic groups of 6 to 12 carbon atoms having a completelyconjugated pi-electron system. It will be understood that in certainembodiments, aryl may be advantageously of limited size such as C₆-C₁₀aryl. Illustrative aryl groups include, but are not limited to, phenyl,naphthylenyl and anthracenyl. The aryl group may be unsubstituted, orsubstituted as described for alkyl or as described in the variousembodiments provided herein.

As used herein, the term “cycloalkyl” refers to a 3 to 15 memberall-carbon monocyclic ring, including an all-carbon 5-member/6-member or6-member/6-member fused bicyclic ring, or a multicyclic fused ring (a“fused” ring system means that each ring in the system shares anadjacent pair of carbon atoms with each other ring in the system) group,where one or more of the rings may contain one or more double bonds butthe cycloalkyl does not contain a completely conjugated pi-electronsystem. It will be understood that in certain embodiments, cycloalkylmay be advantageously of limited size such as C₃-C₁₃, C₃-C₉, C₃-C₆ andC₄-C₆. Cycloalkyl may be unsubstituted, or substituted as described foralkyl or as described in the various embodiments provided herein.Illustrative cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl,cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, norbornyl,norbornenyl, 9H-fluoren-9-yl, and the like. Illustrative examples ofcycloalkyl groups shown in graphical representations include thefollowing entities, in the form of properly bonded moieties:

As used herein, the term “heterocycloalkyl” refers to a monocyclic orfused ring group having in the ring(s) from 3 to 12 ring atoms, in whichat least one ring atom is a heteroatom, such as nitrogen, oxygen orsulfur, the remaining ring atoms being carbon atoms. Heterocycloalkylmay optionally contain 1, 2, 3 or 4 heteroatoms. Heterocycloalkyl mayalso have one of more double bonds, including double bonds to nitrogen(e.g. C═N or N═N) but does not contain a completely conjugatedpi-electron system. It will be understood that in certain embodiments,heterocycloalkyl may be advantageously of limited size such as 3- to7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, and thelike. Heterocycloalkyl may be unsubstituted, or substituted as describedfor alkyl or as described in the various embodiments provided herein.Illustrative heterocycloalkyl groups include, but are not limited to,oxiranyl, thianaryl, azetidinyl, oxetanyl, tetrahydrofuranyl,pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl,1,4-dithianyl, piperazinyl, oxepanyl, 3,4-dihydro-2H-pyranyl,5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2,3,4-tetrahydropyridinyl, and thelike. Illustrative examples of heterocycloalkyl groups shown ingraphical representations include the following entities, in the form ofproperly bonded moieties:

As used herein, the term “heteroaryl” refers to a monocyclic or fusedring group of 5 to 12 ring atoms containing one, two, three or four ringheteroatoms selected from nitrogen, oxygen and sulfur, the remainingring atoms being carbon atoms, and also having a completely conjugatedpi-electron system. It will be understood that in certain embodiments,heteroaryl may be advantageously of limited size such as 3- to7-membered heteroaryl, 5- to 7-membered heteroaryl, and the like.Heteroaryl may be unsubstituted, or substituted as described for alkylor as described in the various embodiments provided herein. Illustrativeheteroaryl groups include, but are not limited to, pyrrolyl, furanyl,thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl,pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, tetrazolyl, triazinyl,pyrazinyl, tetrazinyl, quinazolinyl, quinoxalinyl, thienyl, isoxazolyl,isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl,benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl andcarbazoloyl, and the like. Illustrative examples of heteroaryl groupsshown in graphical representations, include the following entities, inthe form of properly bonded moieties:

As used herein, “hydroxy” or ““hydroxyl” refers to an —OH group.

As used herein, “alkoxy” refers to both an —O-(alkyl) or an—O-(unsubstituted cycloalkyl) group. Representative examples include,but are not limited to, methoxy, ethoxy, propoxy, butoxy,cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and thelike.

As used herein, “aryloxy” refers to an —O-aryl or an —O-heteroarylgroup. Representative examples include, but are not limited to, phenoxy,pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, andthe like, and the like.

As used herein, “mercapto” refers to an —SH group.

As used herein, “alkylthio” refers to an —S-(alkyl) or an—S-(unsubstituted cycloalkyl) group. Representative examples include,but are not limited to, methylthio, ethylthio, propylthio, butylthio,cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, andthe like.

As used herein, “arylthio” refers to an —S-aryl or an —S-heteroarylgroup. Representative examples include, but are not limited to,phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio,and the like.

As used herein, “halo” or “halogen” refers to fluorine, chlorine,bromine or iodine.

As used herein, “cyano” refers to a —CN group.

The term “oxo” represents a carbonyl oxygen. For example, a cyclopentylsubstituted with oxo is cyclopentanone.

As used herein, “bond” refers to a covalent bond.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents.

Where the term “substituted” is used to describe a structural system,the substitution is meant to occur at any valency-allowed position onthe system. In some embodiments, “substituted” means that the specifiedgroup or moiety bears one, two, or three substituents. In otherembodiments, “substituted” means that the specified group or moietybears one or two substituents. In still other embodiments, “substituted”means the specified group or moiety bears one substituent.

As used herein, “optional” or “optionally” means that the subsequentlydescribed event or circumstance may but need not occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not. For example, “wherein each hydrogenatom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3-to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by C₁-C₆ alkyl” meansthat an alkyl may be but need not be present on any of the C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl byreplacement of a hydrogen atom for each alkyl group, and the descriptionincludes situations where the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, ormono- or bicyclic heteroaryl is substituted with an alkyl group andsituations where the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- orbicyclic heteroaryl is not substituted with the alkyl group.

As used herein, “independently” means that the subsequently describedevent or circumstance is to be read on its own relative to other similarevents or circumstances. For example, in a circumstance where severalequivalent hydrogen groups are optionally substituted by another groupdescribed in the circumstance, the use of “independently optionally”means that each instance of a hydrogen atom on the group may besubstituted by another group, where the groups replacing each of thehydrogen atoms may be the same or different. Or for example, wheremultiple groups exist all of which can be selected from a set ofpossibilities, the use of “independently” means that each of the groupscan be selected from the set of possibilities separate from any othergroup, and the groups selected in the circumstance may be the same ordifferent.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which counter ions which may be used in pharmaceuticals.See, generally, S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm.Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts arethose that are pharmacologically effective and suitable for contact withthe tissues of subjects without undue toxicity, irritation, or allergicresponse. A compound described herein may possess a sufficiently acidicgroup, a sufficiently basic group, both types of functional groups, ormore than one of each type, and accordingly react with a number ofinorganic or organic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. Such salts include:

(1) acid addition salts, which can be obtained by reaction of the freebase of the parent compound with inorganic acids such as hydrochloricacid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, andperchloric acid and the like, or with organic acids such as acetic acid,oxalic acid, (D) or (L) malic acid, maleic acid, methane sulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaricacid, citric acid, succinic acid or malonic acid and the like; or

(2) salts formed when an acidic proton present in the parent compoundeither is replaced by a metal ion, e.g., an alkali metal ion, analkaline earth ion, or an aluminum ion; or coordinates with an organicbase such as ethanolamine, diethanolamine, triethanolamine,trimethamine, N-methylglucamine, and the like.

Pharmaceutically acceptable salts are well known to those skilled in theart, and any such pharmaceutically acceptable salt may be contemplatedin connection with the embodiments described herein. Examples ofpharmaceutically acceptable salts include sulfates, pyrosulfates,bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates,dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides,bromides, iodides, acetates, propionates, decanoates, caprylates,acrylates, formates, isobutyrates, caproates, heptanoates, propiolates,oxalates, malonates, succinates, suberates, sebacates, fumarates,maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates,chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates,methoxybenzoates, phthalates, sulfonates, methylsulfonates,propylsulfonates, besylates, xylenesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates,tartrates, and mandelates. Lists of other suitable pharmaceuticallyacceptable salts are found in Remington's Pharmaceutical Sciences, 17thEdition, Mack Publishing Company, Easton, Pa., 1985.

For a compound of Formula I, I-1, Ia, Ib, Ic, II, III, IV, V, VI, VII,VIII, IX, X, XI, XII or XIII that contains a basic nitrogen, apharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, phenylacetic acid,propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid,hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid or glutamic acid, an aromatic acid, such asbenzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, asulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid,methanesulfonic acid, or ethanesulfonic acid, or any compatible mixtureof acids such as those given as examples herein, and any other acid andmixture thereof that are regarded as equivalents or acceptablesubstitutes in light of the ordinary level of skill in this technology.

The disclosure also relates to pharmaceutically acceptable prodrugs ofthe compounds of Formula I, I-1, Ia, Ib, Ic, II, III, IV, V, VI, VII,VIII, IX, X, XI, XII or XIII, and treatment methods employing suchpharmaceutically acceptable prodrugs. The term “prodrug” means aprecursor of a designated compound that, following administration to asubject, yields the compound in vivo via a chemical or physiologicalprocess such as solvolysis or enzymatic cleavage, or under physiologicalconditions (e.g., a prodrug on being brought to physiological pH isconverted to the compound of Formula I, I-1, Ia, Ib, Ic, II, III, IV, V,VI, VII, VIII, IX, X, XI, XII or XIII). A “pharmaceutically acceptableprodrug” is a prodrug that is non-toxic, biologically tolerable, andotherwise biologically suitable for administration to the subject.Illustrative procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985.

The present disclosure also relates to pharmaceutically activemetabolites of compounds of Formula I, I-1, Ia, Ib, Ic, II, III, IV, V,VI, VII, VIII, IX, X, XI, XII or XIII, and uses of such metabolites inthe methods of the disclosure. A “pharmaceutically active metabolite”means a pharmacologically active product of metabolism in the body of acompound of Formula I, I-1, Ia, Ib, Ic, II, III, IV, V, VI, VII, VIII,IX, X, XI, XII or XIII or salt thereof. Prodrugs and active metabolitesof a compound may be determined using routine techniques known oravailable in the art. See, e.g., Bertolini et al., J. Med. Chem. 1997,40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765-767;Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984,13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); andLarsen, Design and Application of Prodrugs, Drug Design and Development(Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).

Any formula depicted herein is intended to represent a compound of thatstructural formula as well as certain variations or forms. For example,a formula given herein is intended to include a racemic form, or one ormore enantiomeric, diastereomeric, or geometric isomers, or a mixturethereof. Additionally, any formula given herein is intended to referalso to a hydrate, solvate, or polymorph of such a compound, or amixture thereof. For example, it will be appreciated that compoundsdepicted by a structural formula containing the symbol “

” include both stereoisomers for the carbon atom to which the symbol “

” is attached, specifically both the bonds “

” and “

” are encompassed by the meaning of “

”. For example, in some exemplary embodiments, certain compoundsprovided herein can be described by the formula

which formula will be understood to encompass compounds having bothstereochemical configurations at the relevant carbon atom, specificallyin this example

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S,¹⁸F, ³⁶Cl, and ¹²⁵I, respectively. Such isotopically labelled compoundsare useful in metabolic studies (preferably with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques[such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT)] including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Further,substitution with heavier isotopes such as deuterium (i.e., ²H) mayafford certain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements. Isotopically labeled compounds of this disclosure andprodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the schemes or in the examples and preparationsdescribed below by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

Any disubstituent referred to herein is meant to encompass the variousattachment possibilities when more than one of such possibilities areallowed. For example, reference to disubstituent -A-B—, where A≠B,refers herein to such disubstituent with A attached to a firstsubstituted member and B attached to a second substituted member, and italso refers to such disubstituent with A attached to the secondsubstituted member and B attached to the first substituted member.

Representative Embodiments

In some embodiments, compounds described herein comprise a moiety of theformula

wherein Z¹-Z⁷ are defined as described herein. In other embodiments,compounds described herein comprise a moiety of the formula

wherein Z¹-Z⁷ are otherwise defined as described herein. In still otherembodiments, compounds described herein comprise a moiety of the formula

In still other embodiments, compounds described herein comprise a moietyof the formula

In still other embodiments, compounds described herein comprise a moietyof the formula

In some embodiments, Z¹, Z⁴ and Z⁷ are N, and Z², Z³, Z⁵ and Z⁶ areC(R¹). In some embodiments, Z¹, Z⁴ and Z⁷ are N, and Z², Z³, Z⁵ and Z⁶are C(R¹⁰), wherein each R¹⁰ is H. In some embodiments, Z¹ and Z³ are N,Z⁷ is NH and Z², Z⁴, Z⁵, and Z⁶ are C(R¹⁰). In some embodiments, Z¹ andZ³ are N, Z⁷ is NH and Z², Z⁴, Z⁵, and Z⁶ are C(R¹⁰), wherein each R¹⁰is H. In some embodiments, Z¹, Z³ and Z⁶ are N, Z⁷ is NH and Z², Z⁴ andZ⁵ are C(R¹⁰). In some embodiments, Z¹, Z³ and Z⁶ are N, Z⁷ is NH andZ², Z⁴ and Z⁵ are C(R¹), wherein each R¹⁰ is H. In some embodiments, Z³is N, Z⁷ is NH and Z¹, Z², Z⁴, Z⁵, and Z⁶ are C(R¹⁰). In someembodiments, Z³ is N, Z⁷ is NH and Z¹, Z², Z⁴, Z⁵, and Z⁶ are C(R¹⁰),wherein each R¹⁰ is H. In some embodiments, Z³ and Z⁶ are N, Z⁷ is NHand Z¹, Z², Z⁴ and Z⁵ are C(R¹⁰). In some embodiments, Z³ and Z⁶ are N,Z⁷ is NH and Z¹, Z², Z⁴ and Z⁵ are C(R¹), wherein each R¹⁰ is H. In someembodiments, Z², Z⁴ and Z⁷ are N and Z¹, Z³, Z⁵ and Z⁶ are C(R¹). Insome embodiments, Z², Z⁴ and Z⁷ are N and Z¹, Z³, Z⁵ and Z⁶ are C(R¹⁰),wherein each R¹¹ is H. In some embodiments, Z¹, Z⁵ and Z⁷ are N and Z²,Z³, Z⁴ and Z⁶ are C(R¹¹). In some embodiments, Z¹, Z⁵ and Z⁷ are N andZ², Z³, Z⁴ and Z⁶ are C(R¹⁰), wherein each R¹⁰ is H. In someembodiments, Z¹, Z², Z⁴ and Z⁷ are N and Z³, Z⁵ and Z⁶ are C(R¹⁰). Insome embodiments, Z¹, Z², Z⁴ and Z⁷ are N and Z³, Z⁵ and Z⁶ are C(R¹⁰),wherein each R¹⁰ is H. In some embodiments, Z¹, Z², Z⁵ and Z⁷ are N andZ³, Z⁴ and Z⁶ are C(R¹⁰). In some embodiments, Z¹, Z², Z⁵ and Z⁷ are Nand Z³, Z⁴ and Z⁶ are C(R¹⁰), wherein each R¹⁰ is H. In someembodiments, Z³, Z⁵ and Z⁶ are N and Z¹, Z², Z⁴ and Z⁷ are C(R¹⁰). Insome embodiments, Z³, Z⁵ and Z⁶ are N and Z¹, Z², Z⁴ and Z⁷ are C(R¹⁰),wherein each R¹⁰ is H. In some embodiments, Z¹, Z⁵, Z⁶ and Z⁷ are N andZ², Z³ and Z⁴ are C(R¹⁰). In some embodiments, Z¹, Z⁵, Z⁶ and Z⁷ are Nand Z², Z³ and Z⁴ are C(R¹⁰) wherein each R¹⁰ is H. In some embodiments,Z¹, Z² and Z⁴ are N and Z³, Z⁵, Z⁶ and Z⁷ are C(R¹⁰). In someembodiments, Z¹, Z² and Z⁴ are N and Z³, Z⁵, Z⁶ and Z⁷ are C(R¹⁰),wherein each R¹⁰ is H. In some embodiments, Z¹, Z³ and Z⁴ are N and Z²,Z⁵, Z⁶ and Z⁷ are C(R¹⁰). In some embodiments, Z¹, Z³ and Z⁴ are N andZ², Z⁵, Z⁶ and Z⁷ are C(R¹⁰), wherein each R¹⁰ is H. In someembodiments, Z³ and Z⁴ are N and Z¹, Z², Z⁵, Z⁶ and Z⁷ are C(R¹⁰). Insome embodiments, Z³ and Z⁴ are N and Z¹, Z², Z⁵, Z⁶ and Z⁷ are C(R¹⁰),wherein each R¹⁰ is H. In some embodiments, Z², Z⁵ and Z⁷ are N and Z¹,Z³, Z⁴ and Z⁶ are C(R¹⁰). In some embodiments, Z², Z⁵ and Z⁷ are N andZ¹, Z³, Z⁴ and Z⁶ are C(R¹⁰), wherein each R¹⁰ is H. In someembodiments, Z³ and Z⁵ are N and Z¹, Z², Z⁴, Z⁶ and Z⁷ are C(R¹⁰). Insome embodiments, Z³ and Z⁵ are N and Z¹, Z², Z⁴, Z⁶ and Z⁷ are C(R¹⁰),wherein each R¹⁰ is H. In some embodiments, Z², Z⁵, Z⁶ and Z⁷ are N andZ¹, Z³ and Z⁴ are C(R¹⁰). In some embodiments, Z², Z⁵, Z⁶ and Z⁷ are Nand Z¹, Z³ and Z⁴ are C(R¹⁰), wherein each R¹⁰ is H.

In some embodiments, X¹ is —N(R⁹)—. In some embodiments, X² is —O—. Insome embodiments, X¹ is —N(R⁹)—, and X² is —O—. In some embodiments, Mis CH or N. In some embodiments, M is N. In some embodiments, M is CH.In some embodiments, M¹ is CH or N. In some embodiments, M¹ is N. Insome embodiments, M¹ is CH.

In some embodiments, R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein eachhydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl and C₆-C₁₀ aryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl or 3- to 7-memberedheterocycloalkyl.

In some embodiments, R¹ is C₁-C₆ alkyl, wherein each hydrogen atom isindependently optionally substituted by deuterium, halogen, —OH, —CN,—OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆alkyl), —N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆alkyl), —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl.

In some embodiments, R¹ is methyl, ethyl, isopropyl,2-hydroxy-2-propryl, 2-hydroxyethyl or 2-fluoroethyl. In someembodiments, R¹ is methyl. In some embodiments, R¹ is ethyl. In someembodiments, R¹ is isopropyl. In some embodiments, R¹ is2-hydroxy-2-propryl. In some embodiments, R¹ is 2-hydroxyethyl. In someembodiments, R¹ is 2-fluoroethyl. In some embodiments, R¹ is D₃C—. Insome embodiments, R¹ is —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl) or —C(O)N(C₁-C₆alkyl). In some embodiments, R¹ is —C(O)NHCH₃. In some embodiments, R¹is —C(O)N(CH₃)₂. In some embodiments, R¹ is cyanomethyl.

In some embodiments, R² is C₁-C₆ alkyl or —C(O)NR⁷R⁸, wherein eachhydrogen atom in C₁-C₆ alkyl is independently optionally substitutedwith one or more moieties selected from group consisting of —F, —OH,—OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), and —N(C₁-C₆ alkyl)₂. In someembodiments, R² is C₁-C₆ alkyl or —C(O)NR⁷R⁸, wherein each hydrogen atomin C₁-C₆ alkyl is independently optionally substituted with one or moremoieties selected from group consisting of —F, —OH, —OC₁-C₆ alkyl, —NH₂,—NH(C₁-C₆ alkyl), and —N(C₁-C₆ alkyl)₂, and R³ is H.

In some embodiments, R³ is C₁-C₆ alkyl or —C(O)NR⁷R⁸, wherein eachhydrogen atom in C₁-C₆ alkyl is independently optionally substitutedwith one or more moieties selected from group consisting of —F, —OH,—OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), and —N(C₁-C₆ alkyl)₂. In someembodiments, R³ is C₁-C₆ alkyl or —C(O)NR⁷R⁸, wherein each hydrogen atomin C₁-C₆ alkyl is independently optionally substituted with one or moremoieties selected from group consisting of —F, —OH, —OC₁-C₆ alkyl, —NH₂,—NH(C₁-C₆ alkyl), and —N(C₁-C₆ alkyl)₂, and R² is H.

In some embodiments, R² and R³ combine to form a C₃-C₆ cycloalkyl. Insome embodiments, R² and R³ combine to form a cyclopentyl ring. In someembodiments, R² and R³ combine to form a cyclohexyl ring. In someembodiments, R² and R³ combine to form a 3- to 7-memberedheterocycloalkyl. In some embodiments, R² and R³ combine to form apyrrolidinyl ring. In some embodiments, R² and R³ combine to form apiperidinyl ring. In some embodiments, R² and R⁶ combine to form apyrrolidine ring. In some embodiments, R² and R⁶ combine to form apiperidinyl ring.

In some embodiments, R⁴ and R⁵ are each independently H, fluoro, chloro,bromo, methyl, ethyl, propyl, isopropyl, —OH, methoxy, ethoxy,isopropoxy, —CN, or —CF₃. In some embodiments, R⁴ is H, fluoro, chloro,bromo, methyl, ethyl, propyl, isopropyl, —OH, methoxy, ethoxy,isopropoxy, —CN, or —CF₃, and R⁵ is H. In some embodiments, R⁴ isfluoro, and R⁵ is H.

In other embodiments, the compound of Formula I, I-1, Ia, Ib, Ic, II,III, IV, V, VI, VII, VIII, IX, X, XI, XII or XIII is selected from thegroup consisting of(7R,13R)-7-ethyl-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(6R,13R)-6-ethyl-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-etheno-pyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(7S,13R)-7-ethyl-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriaza-cyclotridecin-4(5H)-one,(6S,13R)-6-ethyl-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(7R,13R)-11-fluoro-7-(hydroxymethyl)-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(6S,13R)-11-fluoro-6-(hydroxymethyl)-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(7S,13R)-11-fluoro-7-(hydroxymethyl)-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]-benzoxatriazacyclotridecin-4(5H)-one,(6R,13R)-11-fluoro-6-(hydroxymethyl)-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(7R,13R)-11-fluoro-7-(fluoromethyl)-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(7S,13R)-11-fluoro-7-(fluoromethyl)-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(6S,13R)-11-fluoro-6-(fluoromethyl)-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(7R,13R)-7-[(dimethylamino)methyl]-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(6S,13R)-6-[(dimethylamino)methyl]-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriaza-cyclotridecin-4(5H)-one,(7S,13R)-7-(N-methylcarboxamide)-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(7R,13R)-7-(N-methylcarboxamide)-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(6R,13R)-6-(difluoromethyl)-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(6S,13R)-6-(difluoromethyl)-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(7R,13R)-7-(difluoromethyl)-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(13R)-13-ethyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(7S,13R)-7,13-diethyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriaza-cyclotridecin-4(5H)-one,(6S,13R)-6,13-diethyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(13R)-11-fluoro-13-(2-hydroxyethyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriaza-cyclotridecin-4(5H)-one,(13R)-11-fluoro-13-(2-fluoroethyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(13S)-11-fluoro-13-(2-hydroxypropan-2-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriaza-cyclotridecin-4(5H)-one,(7S,13R)-11-fluoro-7-(methoxymethyl)-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(7S,13R)-11-fluoro-7-methyl-13-(²H₃)methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(7R)-7-ethyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(7R)-11-fluoro-7-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(7S)-11-fluoro-7-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,1]benzoxatriazacyclotridecin-4(5H)-one,(6R)-11-fluoro-6-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(6S)-11-fluoro-6-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(7S,13R)-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f]pyrido[2,3-l][1,4,8,10]oxatriazacyclotridecin-4(5H)-one,7-methyl-6,7,14,15-tetrahydro-2H-3,5-(azenometheno)pyrrolo[3,4-f][1,4,8,10]benzoxatriazacyclotridecin-16(13H)-one,(13R)-11-fluoro-13,17-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriaza-cyclotridecin-4(5H)-one,(7S,13R)-11-fluoro-7,13,17-trimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(13R)-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriaza-cyclotridecin-4(5H)-one,(13R)-13,17-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,[(7S,13R)-11-fluoro-7-methyl-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-13-yl]acetonitrile,(7S,13R)-3-ethyl-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(7R,13S)-9-fluoro-7,13-dimethyl-6,7,14,15-tetrahydro-2H-3,5-(azenometheno)pyrrolo[3,4-f][1,4,8,10]benzoxatriaza-cyclotridecin-16(13H)-one,(3aR,9R,17aS)-7-fluoro-9-methyl-1,2,3,3a,9,10,17,17a-octahydro-16H-11,13-ethenocyclopenta[b]pyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-16-one,(3aS,9R,17aR)-7-fluoro-9-methyl-1,2,3,3a,9,10,17,17a-octahydro-16H-11,13-ethenocyclopenta[b]pyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-16-one,(3aR,9R,17aR)-7-fluoro-9-methyl-1,2,3,3a,9,10,17,17a-octahydro-16H-11,13-ethenocyclopenta[b]pyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-16-one,(4aS,10R,18aS)-8-fluoro-10-methyl-2,3,4,4a,10,11,18,18a-octahydro-12,14-ethenodibenzo[b,l]pyrazolo[4,3-f][1,4,8,10]oxatriaza-cyclotridecin-17(1H)-one,(4aR,1bR,18aR)-8-fluoro-10-methyl-2,3,4,4a,10,11,18,18a-octahydro-12,14-ethenodibenzo[b,l]pyrazolo[4,3-f][1,4,8,10]oxatriazacyclotridecin-17(1H)-one,(3aS,9R,17aS)-7-fluoro-9-methyl-1,2,3,3a,9,10,17,17a-octahydro-16H-11,13-ethenocyclopenta[b]pyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-16-one,(4aS,10R,18aR)-8-fluoro-10-methyl-2,3,4,4a,10,11,18,18a-octahydro-12,14-ethenodibenzo[b,l]pyrazolo[4,3-f][1,4,8,10]oxatriazacyclotridecin-17(1H)-one,(3aR,9R,17aS)-7-fluoro-9-methyl-1,2,3,3a,9,10,17,17a-octahydro-16H-11,13-ethenopyrazolo[4,3-J]pyrrolo[3,4-b][1,4,8,10]benzoxatriazacyclotridecin-16-one,(3aS,9R,17aS)-7-fluoro-9-methyl-1,2,3,3a,9,10,17,17a-octahydro-16H-11,13-ethenopyrazolo[4,3-f]pyrrolo[3,4-b][1,4,8,10]benzoxatriazacyclotridecin-16-one,(8R,14R)-12-fluoro-14-methyl-7,8,14,15-tetrahydro-4H,6H-1,16-etheno-5,8-methanopyrazolo[4,3-g][1,5,9,11]benzoxatriaza-cyclotetradecin-4-one,(8S,14R)-12-fluoro-14-methyl-7,8,14,15-tetrahydro-4H,6H-1,16-etheno-5,8-methanopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one,(9R,15R)-13-fluoro-15-methyl-6,7,8,9,15,16-hexahydro-4H-1,17-etheno-5,9-methanopyrazolo[4,3-h][1,6,10,12]benzoxatriazacyclopentadecin-4-one,(9S,15R)-13-fluoro-15-methyl-6,7,8,9,15,16-hexahydro-4H-1,17-etheno-5,9-methanopyrazolo[4,3-h][1,6,10,12]benzoxatriaza-cyclopentadecin-4-one,(14R)-12-fluoro-14-methyl-7,8,14,15-tetrahydro-4H,6H-5,8-ethano-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one,(7S,13R)-7-[(dimethylamino)methyl]-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(7R,13R)-11-fluoro-13-methyl-7-[(methylamino)methyl]-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriaza-cyclotridecin-4(5H)-one,(7S,13R)-11-fluoro-13-methyl-7-[(pyrrolidin-1-yl)methyl]-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,(7R,13R)-7-ethyl-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-4(5H)-one,(7S,13S)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-4(5H)-one,(7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-4(5H)-one,(7S)-11-fluoro-N,7-dimethyl-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-13-carboxamideand(7S)-11-fluoro-N,N,7-trimethyl-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-13-carboxamide

or a pharmaceutically acceptable salt thereof.

The following represent illustrative embodiments of compounds of theformula I, I-1, Ia, Ib, Ic, II, III, IV, V, VI, VII, VIII, IX, X, XI,XII and XIII:

Compound Structure Name 1

(7R,13R)-7-ethyl-11- fluoro-13-methyl- 6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10] benzoxatriazacyclotridecin- 4(5H)-one 2

(6R,13R)-6-ethyl-11- fluoro-13-methyl- 6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10] benzoxatriazacyclotridecin- 4(5H)-one 3

(7S,13R)-7-ethyl-11- fluoro-13-methyl- 6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10] benzoxatriazacyclotridecin- 4(5H)-one 4

(6S,13R)-6-ethyl-11- fluoro-13-methyl- 6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10] benzoxatriazacyclotridecin- 4(5H)-one 5

(7R,13R)-11-fluoro-7- (hydroxymethyl)- 13-methyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin- 4(5H)-one 6

(6S,13R)-11-fluoro-6- (hydroxymethyl)- 13-methyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin- 4(5H)-one 7

(7S,13R)-11-fluoro-7- (hydroxymethyl)- 13-methyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin- 4(5H)-one 8

(6R,13R)-11-fluoro-6- (hydroxymethyl)- 13-methyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin- 4(5H)-one 9

(7R,13R)-11-fluoro-7- (fluoromethyl)- 13-methyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin- 4(5H)-one 10

(7S,13R)-11-fluoro-7- (fluoromethyl)- 13-methyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin- 4(5H)-one 11

(6S,13R)-11-fluoro-6- (fluoromethyl)- 13-methyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin- 4(5H)-one 12

(7R,13R)-7- [(dimethylamino)methyl]- 11-fluoro- 13-methyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin- 4(5H)-one 13

(6S,13R)-6- [(dimethylamino)methyl]- 11-fluoro- 13-methyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin- 4(5H)-one 14

(7S,13R)-7- (N-methylcarboxamide)- 11-fluoro- 13-methyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin- 4(5H)-one 15

(7R,13R)-7- (N-methylcarboxamide)- 11-fluoro- 13-methyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin- 4(5H)-one 16

(6R,13R)-6- (difluoromethyl)- 11-fluoro- 13-methyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin- 4(5H)-one 17

(6S,13R)-6- (difluoromethyl)- 11-fluoro- 13-methyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin- 4(5H)-one 18

(7R,13R)-7- (difluoromethyl)- 11-fluoro- 13-methyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin- 4(5H)-one 19

(13R)-13-ethyl- 11-fluoro- 6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10] benzoxatriazacyclotridecin- 4(5H)-one20

(7S,13R)-7,13-diethyl- 11-fluoro- 6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10] benzoxatriazacyclotridecin- 4(5H)-one21

(6S,13R)-6,13-diethyl- 11-fluoro- 6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10] benzoxatriazacyclotridecin- 4(5H)-one22

(13R)-11-fluoro-13- (2-hydroxyethyl)- 6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10] benzoxatriazacyclotridecin- 4(5H)-one23

(13R)-11-fluoro-13- (2-fluoroethyl)- 6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10] benzoxatriazacyclotridecin- 4(5H)-one24

(13S)-11-fluoro-13- (2-hydroxypropan-2-yl)- 6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10] benzoxatriazacyclotridecin- 4(5H)-one25

(7S,13R)-11-fluoro-7- (methoxymethyl)- 13-methyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin- 4(5H)-one 26

(7S,13R)-11-fluoro-7- methyl-13-(²H₃)methyl- 6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10] benzoxatriazacyclotridecin- 4(5H)-one27

(7R)-7-ethyl-11-fluoro- 6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f][1,4,8,10] benzoxatriazacyclotridecin- 4(5H)-one 28

(7R)-11-fluoro-7-methyl- 6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10] benzoxatriazacyclotridecin- 4(5H)-one29

(7S)-11-fluoro-7-methyl- 6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10] benzoxatriazacyclotridecin- 4(5H)-one30

(6R)-11-fluoro-6-methyl- 6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10] benzoxatriazacyclotridecin- 4(5H)-one31

(6S)-11-fluoro-6-methyl- 6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10] benzoxatriazacyclotridecin- 4(5H)-one32

(7S,13R)-7,13-dimethyl- 6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f]pyrido[2,3-l] [1,4,8,10] oxatriazacyclotridecin- 4(5H)-one 33

7-methyl- 6,7,14,15-tetrahydro-2H- 3,5-(azenometheno)pyrrolo[3,4-f][1,4,8,10] benzoxatriazacyclotridecin- 16(13H)-one 34

(13R)-11-fluoro-13,17- dimethyl- 6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10] benzoxatriazacyclotridecin- 4(5H)-one35

(7S,13R)-11-fluoro- 7,13,17-trimethyl- 6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10] benzoxatriazacyclotridecin- 4(5H)-one36

(13R)-13-methyl- 6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f][1,4,8,10] benzoxatriazacyclotridecin- 4(5H)-one 37

(13R)-13,17-dimethyl- 6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f][1,4,8,10] benzoxatriazacyclotridecin- 4(5H)-one 38

[(7S,13R)-11-fluoro- 7-methyl-4-oxo- 4,5,6,7,13,14- hexahydro-1,15-ethenopyrazolo [4,3-f] [1,4,8,10] benzoxatriazacyclotridecin-13-yl]acetonitrile 39

(7S,13R)-3-ethyl- 11-fluoro- 7,13-dimethyl- 6,7,13,14-tetrahydro-1,15-ethenopyrazolo [4,3-f] [1,4,8,10] benzoxatriazacyclotridecin- 4(5H)-one40

(7R,13S)-9-fluoro- 7,13-dimethyl- 6,7,14,15-tetrahydro- 2H-3,5-(azenometheno)pyrrolo [3,4-f] [1,4,8,10] benzoxatriazacyclotridecin-16(13H)-one 41

(3αR,9R,17αS)-7-fluoro- 9-methyl- 1,2,3,3α,9,10,17,17α-octahydro-16H-11,13- ethenocyclopenta[b] pyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin- 16-one 42

(3αS,9R,17αR)-7-fluoro- 9-methyl- 1,2,3,3α,9,10,17,17α-octahydro-16H-11,13- ethenocyclopenta[b] pyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin- 16-one 43

(3αR,9R,17αR)-7-fluoro- 9-methyl- 1,2,3,3α,9,10,17,17α-octahydro-16H-11,13- ethenocyclopenta[b] pyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin- 16-one 44

(4αS,10R,18αS)-8-fluoro- 10-methyl- 2,3,4,4α,10,11,18,18α-octahydro-12,14- ethenodibenzo[b,l] pyrazolo[4,3-f] [1,4,8,10]oxatriazacyclotridecin- 17(1H)-one 45

(4αR,10R,18αR)-8-fluoro- 10-methyl- 2,3,4,4α,10,11,18,18α-octahydro-12,14- ethenodibenzo[b,l] pyrazolo[4,3-f] [1,4,8,10]oxatriazacyclotridecin- 17(1H)-one 46

(3αS,9R,17αS)-7-fluoro- 9-methyl- 1,2,3,3α,9,10,17,17α-octahydro-16H-11,13- ethenocyclopenta[b] pyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin- 16-one 47

(4αS,10R,18αR)-8-fluoro- 10-methyl- 2,3,4,4α,10,11,18,18α-octahydro-12,14- ethenodibenzo[b,l] pyrazolo[4,3-f] [1,4,8,10]oxatriazacyclotridecin- 17(1H)-one 48

(3αR,9R,17αS)-7-fluoro- 9-methyl- 1,2,3,3α,9,10,17,17α-octahydro-16H-11,13- ethenopyrazolo[4,3-f] pyrrolo[3,4-b] [1,4,8,10]benzoxatriazacyclotridecin- 16-one 49

(3αS,9R,17αS)-7-fluoro- 9-methyl- 1,2,3,3α,9,10,17,17α-octahydro-16H-11,13- ethenopyrazolo[4,3-f] pyrrolo[3,4-b] [1,4,8,10]benzoxatriazacyclotridecin- 16-one 50

(8R,14R)-12-fluoro- 14-methyl- 7,8,14,15-tetrahydro-4H,6H-1,16-etheno-5,8- methanopyrazolo[4,3-g] [1,5,9,11]benzoxatriazacyclotetradecin- 4-one 51

(8S,14R)-12-fluoro- 14-methyl- 7,8,14,15-tetrahydro-4H,6H-1,16-etheno-5,8- methanopyrazolo[4,3-g] [1,5,9,11]benzoxatriazacyclotetradecin- 4-one 52

(9R,15R)-13-fluoro- 15-methyl- 6,7,8,9,15,16-hexahydro-4H-1,17-etheno-5,9- methanopyrazolo[4,3-h] [1,6,10,12]benzoxatriazacyclopentadecin- 4-one 53

(9S,15R)-13-fluoro- 15-methyl- 6,7,8,9,15,16-hexahydro-4H-1,17-etheno-5,9- methanopyrazolo[4,3-h] [1,6,10,12]benzoxatriazacyclopentadecin- 4-one 54

(14R)-12-fluoro- 14-methyl- 7,8,14,15-tetrahydro- 4H,6H-5,8-etheno-1,16-ethenopyrazolo[4,3-g] [1,5,9,11] benzoxatriazacyclotetradecin- 4-one 55

(7S,13R)-7- [(dimethylamino)methyl]- 11-fluoro- 13-methyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin- 4(5H)-one 56

(7R,13R)-11-fluoro- 13-methyl-7- [(methylamino)methyl]-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin- 4(5H)-one 57

(7S,13R)-11-fluoro- 13-methyl-7- [(pyrrolidin-1-yl)methyl]-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin- 4(5H)-one 58

(7R,13R)-7-ethyl-11-fluoro- 13-methyl- 6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] pyrido[3,2-l] [1,4,8,10] oxatriazacyclotridecin-4(5H)-one 59

(7S,13S)-11-fluoro- 7,13-dimethyl- 6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] pyrido[3,2-l] [1,4,8,10] oxatriazacyclotridecin-4(5H)-one 60

(7S,13R)-11-fluoro- 7,13-dimethyl- 6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] pyrido[3,2-l] [1,4,8,10] oxatriazacyclotridecin-4(5H)-one 61

(7S)-11-fluoro-N,7-dimethyl- 4-oxo-4,5,6,7,13,14- hexahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10] benzoxatriazacyclotridecine-13-carboxamide 62

(7S)-11-fluoro-N,N,7- trimethyl-4-oxo- 4,5,6,7,13,14- hexahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10] benzoxatriazacyclotridecine-13-carboxamide

Those skilled in the art will recognize that the species listed orillustrated herein are not exhaustive, and that additional specieswithin the scope of these defined terms may also be selected.

Pharmaceutical Compositions

For treatment purposes, pharmaceutical compositions comprising thecompounds described herein may further comprise one or morepharmaceutically-acceptable excipients. A pharmaceutically-acceptableexcipient is a substance that is non-toxic and otherwise biologicallysuitable for administration to a subject. Such excipients facilitateadministration of the compounds described herein and are compatible withthe active ingredient. Examples of pharmaceutically-acceptableexcipients include stabilizers, lubricants, surfactants, diluents,anti-oxidants, binders, coloring agents, bulking agents, emulsifiers, ortaste-modifying agents. In preferred embodiments, pharmaceuticalcompositions according to the invention are sterile compositions.Pharmaceutical compositions may be prepared using compounding techniquesknown or that become available to those skilled in the art.

Sterile compositions are also contemplated by the invention, includingcompositions that are in accord with national and local regulationsgoverning such compositions.

The pharmaceutical compositions and compounds described herein may beformulated as solutions, emulsions, suspensions, or dispersions insuitable pharmaceutical solvents or carriers, or as pills, tablets,lozenges, suppositories, sachets, dragees, granules, powders, powdersfor reconstitution, or capsules along with solid carriers according toconventional methods known in the art for preparation of various dosageforms. Pharmaceutical compositions of the invention may be administeredby a suitable route of delivery, such as oral, parenteral, rectal,nasal, topical, or ocular routes, or by inhalation. Preferably, thecompositions are formulated for intravenous or oral administration.

For oral administration, the compounds the invention may be provided ina solid form, such as a tablet or capsule, or as a solution, emulsion,or suspension. To prepare the oral compositions, the compounds of theinvention may be formulated to yield a dosage of, e.g., from about 0.1mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mgdaily, or about 250 mg to 1 g daily. Oral tablets may include the activeingredient(s) mixed with compatible pharmaceutically acceptableexcipients such as diluents, disintegrating agents, binding agents,lubricating agents, sweetening agents, flavoring agents, coloring agentsand preservative agents. Suitable inert fillers include sodium andcalcium carbonate, sodium and calcium phosphate, lactose, starch, sugar,glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, andthe like. Exemplary liquid oral excipients include ethanol, glycerol,water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starchglycolate, microcrystalline cellulose, and alginic acid are exemplarydisintegrating agents. Binding agents may include starch and gelatin.The lubricating agent, if present, may be magnesium stearate, stearicacid, or talc. If desired, the tablets may be coated with a materialsuch as glyceryl monostearate or glyceryl distearate to delay absorptionin the gastrointestinal tract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, active ingredient(s) may be mixed witha solid, semi-solid, or liquid diluent. Soft gelatin capsules may beprepared by mixing the active ingredient with water, an oil, such aspeanut oil or olive oil, liquid paraffin, a mixture of mono anddi-glycerides of short chain fatty acids, polyethylene glycol 400, orpropylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions, or syrups, or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

For parenteral use, including intravenous, intramuscular,intraperitoneal, intranasal, or subcutaneous routes, the agents of theinvention may be provided in sterile aqueous solutions or suspensions,buffered to an appropriate pH and isotonicity or in parenterallyacceptable oil. Suitable aqueous vehicles include Ringer's solution andisotonic sodium chloride. Such forms may be presented in unit-dose formsuch as ampoules or disposable injection devices, in multi-dose formssuch as vials from which the appropriate dose may be withdrawn, or in asolid form or pre-concentrate that can be used to prepare an injectableformulation. Illustrative infusion doses range from about 1 to 1000μg/kg/minute of agent admixed with a pharmaceutical carrier over aperiod ranging from several minutes to several days.

For nasal, inhaled, or oral administration, the inventive pharmaceuticalcompositions may be administered using, for example, a spray formulationalso containing a suitable carrier. The inventive compositions may beformulated for rectal administration as a suppository.

For topical applications, the compounds of the present invention arepreferably formulated as creams or ointments or a similar vehiclesuitable for topical administration. For topical administration, theinventive compounds may be mixed with a pharmaceutical carrier at aconcentration of about 0.1% to about 10% of drug to vehicle. Anothermode of administering the agents of the invention may utilize a patchformulation to effect transdermal delivery.

As used herein, the terms “treat” or “treatment” encompass both“preventative” and “curative” treatment. “Preventative” treatment ismeant to indicate a postponement of development of a disease, a symptomof a disease, or medical condition, suppressing symptoms that mayappear, or reducing the risk of developing or recurrence of a disease orsymptom. “Curative” treatment includes reducing the severity of orsuppressing the worsening of an existing disease, symptom, or condition.Thus, treatment includes ameliorating or preventing the worsening ofexisting disease symptoms, preventing additional symptoms fromoccurring, ameliorating or preventing the underlying systemic causes ofsymptoms, inhibiting the disorder or disease, e.g., arresting thedevelopment of the disorder or disease, relieving the disorder ordisease, causing regression of the disorder or disease, relieving acondition caused by the disease or disorder, or stopping the symptoms ofthe disease or disorder.

The term “subject” refers to a mammalian patient in need of suchtreatment, such as a human.

Exemplary diseases include cancer, pain, neurological diseases,autoimmune diseases, and inflammation. Cancer includes, for example,lung cancer, colon cancer, breast cancer, prostate cancer,hepatocellular carcinoma, renal cell carcinoma, gastric andesophago-gastric cancers, glioblastoma, head and neck cancers,inflammatory myofibroblastic tumors, and anaplastic large cell lymphoma.Pain includes, for example, pain from any source or etiology, includingcancer pain, pain from chemotherapeutic treatment, nerve pain, pain frominjury, or other sources. Autoimmune diseases include, for example,rheumatoid arthritis, Sjogren syndrome, Type I diabetes, and lupus.Exemplary neurological diseases include Alzheimer's Disease, Parkinson'sDisease, Amyotrophic lateral sclerosis, and Huntington's disease.Exemplary inflammatory diseases include atherosclerosis, allergy, andinflammation from infection or injury.

In one aspect, the compounds and pharmaceutical compositions of theinvention specifically target tyrosine receptor kinases, in particularMET, ALK, AXL, TRKs, and JAKs. Thus, these compounds and pharmaceuticalcompositions can be used to prevent, reverse, slow, or inhibit theactivity of one or more of these kinases. In preferred embodiments,methods of treatment target cancer. In other embodiments, methods arefor treating lung cancer or non-small cell lung cancer.

In the inhibitory methods of the invention, an “effective amount” meansan amount sufficient to inhibit the target protein. Measuring suchtarget modulation may be performed by routine analytical methods such asthose described below. Such modulation is useful in a variety ofsettings, including in vitro assays. In such methods, the cell ispreferably a cancer cell with abnormal signaling due to upregulation ofMET, ALK, AXL, TRKs, and/or JAKs.

In treatment methods according to the invention, an “effective amount”means an amount or dose sufficient to generally bring about the desiredtherapeutic benefit in subjects needing such treatment. Effectiveamounts or doses of the compounds of the invention may be ascertained byroutine methods, such as modeling, dose escalation, or clinical trials,taking into account routine factors, e.g., the mode or route ofadministration or drug delivery, the pharmacokinetics of the agent, theseverity and course of the infection, the subject's health status,condition, and weight, and the judgment of the treating physician. Anexemplary dose is in the range of about from about 0.1 mg to 1 g daily,or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250mg to 1 g daily. The total dosage may be given in single or divideddosage units (e.g., BID, TID, QID).

Once improvement of the patient's disease has occurred, the dose may beadjusted for preventative or maintenance treatment. For example, thedosage or the frequency of administration, or both, may be reduced as afunction of the symptoms, to a level at which the desired therapeutic orprophylactic effect is maintained. Of course, if symptoms have beenalleviated to an appropriate level, treatment may cease. Patients may,however, require intermittent treatment on a long-term basis upon anyrecurrence of symptoms. Patients may also require chronic treatment on along-term basis.

Drug Combinations

The inventive compounds described herein may be used in pharmaceuticalcompositions or methods in combination with one or more additionalactive ingredients in the treatment of the diseases and disordersdescribed herein. Further additional active ingredients include othertherapeutics or agents that mitigate adverse effects of therapies forthe intended disease targets. Such combinations may serve to increaseefficacy, ameliorate other disease symptoms, decrease one or more sideeffects, or decrease the required dose of an inventive compound. Theadditional active ingredients may be administered in a separatepharmaceutical composition from a compound of the present invention ormay be included with a compound of the present invention in a singlepharmaceutical composition. The additional active ingredients may beadministered simultaneously with, prior to, or after administration of acompound of the present invention.

Combination agents include additional active ingredients are those thatare known or discovered to be effective in treating the diseases anddisorders described herein, including those active against anothertarget associated with the disease. For example, compositions andformulations of the invention, as well as methods of treatment, canfurther comprise other drugs or pharmaceuticals, e.g., other activeagents useful for treating or palliative for the target diseases orrelated symptoms or conditions. For cancer indications, additional suchagents include, but are not limited to, kinase inhibitors, such as EGFRinhibitors (e.g., erlotinib, gefitinib), Raf inhibitors (e.g.,vemurafenib), VEGFR inhibitors (e.g., sunitinib), ALK inhibitors (e.g.,crizotinib) standard chemotherapy agents such as alkylating agents,antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors,platinum drugs, mitotic inhibitors, antibodies, hormone therapies, orcorticosteroids. For pain indications, suitable combination agentsinclude anti-inflammatories such as NSAIDs. The pharmaceuticalcompositions of the invention may additional comprise one or more ofsuch active agents, and methods of treatment may additionally compriseadministering an effective amount of one or more of such active agents.

Chemical Synthesis

Exemplary chemical entities useful in methods of the invention will nowbe described by reference to illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Furthermore, one of skill in the art will recognizethat the transformations shown in the schemes below may be performed inany order that is compatible with the functionality of the particularpendant groups.

Abbreviations

The examples described herein use materials, including but not limitedto, those described by the following abbreviations known to thoseskilled in the art:

g grams eq equivalents mmol millimoles mL milliliters EtOAc ethylacetate MHz megahertz ppm parts per million δ chemical shift s singlet ddoublet t triplet q quartet quin quintet br broad m multiplet Hz hertzTHF tetrahydrofuran ° C. degrees Celsius PE petroleum ether EA ethylacetate R_(f) retardation factor N normal J coupling constant DMSO-d₆deuterated dimethyl sulfoxide n-BuOH n-butanol DIEAn,n-diisopropylethylamine TMSCl trimethylsilyl chloride min minutes hrhours Me methyl Et ethyl i-Pr isopropyl TLC thin layer chromatography Mmolar Compd# compound number MS mass spectrum m/z mass-to-charge ratioMs methanesulfonyl FDDP pentafluorophenyl diphenylphosphinate Boctert-butyloxycarbonyl TFA trifluoroacetic acid Tos toluenesulfonyl DMAP4-(dimethylamino)pyridine μM micromolar ATP adenosine triphosphate IC₅₀half maximal inhibitory concentration U/mL units of activity permilliliter HOBt hydroxybenzotriazol MOM methoxymethy DIPEAdiisopropylethylamine Deoxo-Fluor bis(2-methoxyethyl)aminosulfurtrifluoride Hunig's base diisopropylethylamine DIAD diisopropylazodicarboxylate TFAA Trifluoroacetic acid SEMtrimethylsilylethyoxymethyl DMF dimethylformamide DCM dichloromethaneDEAD diethyl azodicarboxylate MeTHF 2-methyltetrahydrofuran

General Method A.

Preparation of ethyl(R)-5-((1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate(A-1)

Step 1. Preparation of(R)—N-(5-fluoro-2-hydroxybenzylidene)-2-methylpropane-2-sulfinamide(A-1-3)

To a solution of (R)-2-methylpropane-2-sulfinamide (Sigma-Aldrich, 20.00g, 165.02 mmol, 1.00 eq.) and 5-fluoro-2-hydroxybenzaldehyde(Sigma-Aldrich, 23.12 g, 165.02 mmol, 1.00 eq.) in dichloromethane(200.00 mL) was added Cs₂CO₃ (161.30 g, 495.06 mmol, 3.00 eq.). Themixture was stirred at ambient temperature for 16 hours. The reactionmixture was quenched by addition of water (200 mL) at 0° C. and thenextracted with EtOAc (200 mL×4). The combined organic layers were washedwith brine (500 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by a silica gel column eluting with petroleumether/ethyl acetate from 20:1 to 1:1 to provide A-1-3 (18.00 g, 73.98mmol, 44.83% yield) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ ppm 8.66(s, 1H), 7.19 (dt, J=2.4, 5.2 Hz, 2H), 7.03-6.96 (m, 1H), 1.29 (s, 9H).

Step 2. Preparation of(R)—N—((R)-1-(5-fluoro-2-hydroxyphenyl)ethyl)-2-methylpropane-2-sulfinamide(A-1-4R)

To a solution of A-1-3 (6.00 g, 24.66 mmol, 1.00 eq.) in THF (50.00 mL)was added a solution of MeMgBr in THF (2M, 61.7 mL, 123.30 mmol, 5.00eq.) drop-wise at −65° C. under N₂. Then the mixture was warmed toambient temperature and stirred for 18 hours. The reaction mixture wasquenched by addition of water (20 mL) at 0° C., and the mixture wasextracted with EtOAc (20 mL×3). The combined organic layers were washedwith brine (50 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by a silica gel eluting withpetroleum ether/ethyl acetate from 50/1 to 1:1) to give A-1-4R (Rf: 0.5,PE:EA=1:1) (1.8 g, 28% yield) and A-1-4S (Rf: 0.4, PE:EA=1:1). ¹HNMR ofA-1-4R (CDCl₃, 400 MHz) δ 9.34 (s, 1H), 6.76 (dd, J=2.8, 8.8 Hz, 1H),6.54 (dt, J=2.9, 8.5 Hz, 1H), 6.38 (dd, J=4.8, 8.8 Hz, 1H), 5.27 (d,J=8.0 Hz, 1H), 4.36 (quin, J=7.2 Hz, 1H), 1.52 (d, J=7.0 Hz, 3H), 1.29(s, 9H). ¹HNMR of A-1-4S (CDCl₃, 400 MHz) 8.81 (s, 1H), 6.88 (dd, J=2.6,9.2 Hz, 1H), 6.84-6.76 (m, 1H), 6.76-6.70 (m, 1H), 4.75-4.63 (m, 1H),4.26 (d, J=4.5 Hz, 1H), 1.58 (d, J=6.8 Hz, 3H), 1.27 (s, 9H).

Step 3. Preparation of (R)-2-(1-aminoethyl)-4-fluorophenol (A-1-5)

A solution of A-1-4R (1.80 g, 6.94 mmol, 1.00 eq.) in HCl/EtOAc (20.00mL, 4N) was stirred at ambient temperature for 2 hours, and then themixture was concentrated to provide A-1-5 as a white solid HCl salt(1.10 g, 5.74 mmol, 82.70% yield). ¹HNMR (DMSO-d₆, 400 MHz) δ 10.24 (s,1H), 8.48 (br. s., 3H), 7.31 (dd, J=2.9, 9.7 Hz, 1H), 7.05-6.99 (m, 1H),6.98-6.93 (m, 1H), 4.59-4.45 (m, 1H), 1.46 (d, J=6.8 Hz, 3H).

Step 4. Preparation of ethyl5-oxo-4H-pyrazolo[1,5-a]pyrimidine-3-carboxylate (A-1-7)

To a mixture of ethyl 5-amino-1H-pyrazole-4-carboxylate (150.00 g, 1.08mmol) and ethyl (E)-3-ethoxyprop-2-enoate (292.16 g, 2.03 mol) in DMF(3.2 L) was added Cs₂CO₃ (656.77 g, 2.02 mol) in one portion at 20° C.under N₂. The mixture was stirred at 110° C. for 6 h. TLC (PE:EtOAc=1:1)showed the reaction was completed. The mixture was cooled to 20° C. andfiltered through a celite pad. The filter cake was washed with ethylacetate (3×30 mL). The filtrate was added to H₂O (2 L) and acidifiedwith HOAc to pH=4. The resultant precipitate was filtered to affordA-1-7 (173.00 g, 834.98 mmol, 86.36% yield) as a white solid: ¹H NMR(400 MHz, DMSO-d₆) δ 8.54 (d, J=7.91 Hz, 1H), 8.12 (s, 1H), 6.13 (d,J=7.91 Hz, 1H), 4.27 (q, J=7.11 Hz, 2H), 1.28 (t, J=7.09 Hz, 3H).

Step 5: Preparation of 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate(A-1-8)

To a mixture of A-1-7 (158.00 g, 762.59 mmol) in MeCN (1.6 L) was addedPOCl₃(584.64 g, 3.81 mol) at 20° C. under N₂. The mixture was stirred at100° C. for 2 h. TLC (PE:EA=1:1) showed the reaction was completed. Themixture was cooled to 20° C. and poured into ice-water (5000 mL) inportions at 0° C. and stirred for 20 min. The precipitate was filteredand dried to afford A-1-8 (110.00 g, 487.52 mmol, 63.93% yield) as awhite solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.33 (d, J=7.28 Hz, 1H), 8.66(s, 1H), 7.41 (d, J=7.15 Hz, 1H), 4.31 (q, J=7.15 Hz, 2H), 1.32 (t,J=7.09 Hz, 3H).

Step 6. Preparation of ethyl(R)-5-((1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate(A-1)

To a solution of A-1-5 (1.10 g, 7.09 mmol, 1.00 eq.) and A-1-8 (1.60 g,7.09 mmol, 1.00 eq.) in n-BuOH (30.00 mL) was added DIEA (5.50 g, 42.53mmol, 6.00 eq.). The mixture was stirred at 120° C. for 2 hrs. Thereaction mixture was quenched by addition of water (20 mL) at ambienttemperature, and extracted with EtOAc (20 mL×3). The combined organiclayers were washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=10/1 to 1:3) to provide A-1 (1.15 g, 3.31mmol, 46.69% yield, ee>97% purity) as a white solid.

Preparation of ethyl(R)-5-((1-(5-fluoro-2-hydroxyphenyl)propyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate(A-2)

General method A was followed for the preparation of A-2 using EtMgBr instep 2.

Preparation of(R)—N—((R)-1-(5-fluoro-2-hydroxyphenyl)-3-hydroxypropyl)-2-methylpropane-2-sulfinamide(A-3-5)

Step 1. To a suspension of Zn (6.72 g, 102.75 mmol, 5.00 eq.) inanhydrous THF (50 mL) in a dry apparatus was added TMSCl (446.51 mg,4.11 mmol, 0.20 eq.) at 25° C. drop-wise. The mixture was stirred for 10min followed by heating under nitrogen to 40-50° C. To the mixture wasadded ethyl 2-bromoacetate (10.30 g, 61.65 mmol, 3.00 eq.) in anhydrousTHF (500 mL) drop-wise over 20 min, and then the reaction was stirred at40-50° C. for 30 min. The black mixture was cooled to 0° C. and asolution of A-1-3 (5.00 g, 20.55 mmol, 1.00 eq.) in THF (500 mL) wasadded. The reaction was stirred at 25° C. for 2 hr, quenched withsaturated NH₄Cl (100 mL), and extracted with EtOAc (300 mL×3). Thecombined organic layers were washed with water (300 mL×2) and brine (300mL×2), dried over anhydrous Na₂SO₄, filtered and concentrated. Theresidue was purified with a silica gel column (100-200 mesh) elutingwith petroleum ether/ethyl acetate from 50/1, 10/1 to afford A-3-4S(4.35 g, 13.13 mmol, 63.87% yield) and A-3-4R (0.52 g, 16.35% yield) aswhite solids. ¹HNMR of A-3-4S: (400 MHz, CHLOROFORM-d) δ 8.77 (s, 1H),6.90 (dd, J=3.0, 9.0 Hz, 1H), 6.86-6.80 (m, 1H), 6.78-6.72 (m, 1H), 5.33(d, J=5.0 Hz, 1H), 4.97-4.90 (m, 1H), 4.21-4.14 (m, 2H), 3.03-2.94 (m,1H), 2.93-2.84 (m, 1H), 1.29-1.24 (m, 12H); ¹HNMR of A-3-4R: (400 MHz,CHLOROFORM-d) δ 9.43 (s, 1H), 6.79 (dd, J=2.9, 8.7 Hz, 1H), 6.45 (dt,J=3.0, 8.5 Hz, 1H), 6.16 (dd, J=4.6, 8.9 Hz, 1H), 5.53 (d, J=9.8 Hz,1H), 4.65 (dt, J=5.3, 9.8 Hz, 1H), 4.13-4.07 (m, 2H), 3.01 (dd, J=9.7,15.4 Hz, 1H), 2.63 (dd, J=5.1, 15.4 Hz, 1H), 1.29-1.24 (m, 12H).

Step 2. To a solution of A-3-4R (500.00 mg, 1.51 mmol, 1.00 eq.) inanhydrous THF (5.00 mL) was added LiBH₄ (131.44 mg, 6.04 mmol, 4.00 eq.)at 0° C. portion-wise. The mixture was stirred at ambient temperaturefor 2 hrs. The reaction mixture was quenched with saturated NH₄Cl (50mL), and then diluted by EtOAc (100 mL) and extracted with EtOAc (100mL×3). The combined organic layers were washed with brine (50 mL), dryover Na₂SO₄, filtered and concentrated to provide A-3-5 (360.00 mg, 1.24mmol, 82.39% yield) as a white solid. ¹HNMR (400 MHz, CHLOROFORM-d) δ9.13 (br. s., 1H), 6.79 (dd, J=2.8, 8.7 Hz, 1H), 6.53 (dt, J=3.0, 8.5Hz, 1H), 6.27 (dd, J=4.7, 8.7 Hz, 1H), 5.19 (d, J=9.2 Hz, 1H), 4.42 (q,J=7.7 Hz, 1H), 3.71 (td, J=5.7, 10.8 Hz, 1H), 3.61-3.46 (m, 1H),2.27-2.09 (m, 1H), 1.97 (dt, J=6.5, 13.0 Hz, 1H), 1.28 (s, 9H).

Preparation of ethyl(R)-5-((1-(5-fluoro-2-hydroxyphenyl)-3-hydroxypropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate(A-3)

General method A was followed for the preparation of A-3 using A-3-5 instep 3.

Preparation of (S)-2-(1-amino-2-hydroxy-2-methylpropyl)-4-fluorophenol(A-4-6)

Step 1. To a solution of 2-bromo-4-fluorophenol (Sigma-Aldrich, 13.00 g,68.06 mmol, 1.00 eq.) in THF (100.00 mL) was added NaH (2.72 g, 60% inoil, 68.06 mmol, 1.00 eq.) at 0° C. under N₂ for 5 hours, followed byaddition of MOMCl (3.02 g, 37.51 mmol, 0.55 eq.). The mixture wasstirred at 16° C. for 10 hours, quenched by water (200 ml), andextracted with EtOAc (100 ml×3). The combined organic layers were washedwith brine (200 ml), dried over Na₂SO₄, and concentrated to give A-4-1(9.00 g, 38.29 mmol, 56.26% yield) as an oil.

Step 2. To a solution of A-4-1 (14.00 g, 59.56 mmol, 1.00 eq.) inanhydrous THF (140.00 mL) was added i-PrMgCl—LiCl in THF (1.3 M, 45.82mL, 1.00 eq.) drop-wise at −78° C. in 30 min under N₂. The mixture waswarmed to 25° C. for 1.5 h, and the resulting mixture was addeddrop-wise to diethyl oxalate (43.39 g, 296.90 mmol, 5.00 eq.) in THF(140 ml) at −30° C. in 20 min under N₂. The mixture was warmed to 25° C.for 1.5 hr. TLC showed the starting material was consumed completely.The reaction was quenched with the addition of water (200 mL) slowly,and stirred for 10 min. The organic layer was separated and the aqueousphase was extracted with ethyl acetate (500 mL×3). The combined organiclayers were washed with saturated brine (500 mL), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified bysilica gel chromatography eluting with petroleum ether/ethyl acetatefrom 50/1 to 10/1) to afford A-4-2 (5.70 g, 23.53 mmol, 39.6% yield) asa yellow oil. ¹HNMR (400 MHz, CHLOROFORM-d) δ 7.56 (dd, J=3.2, 8.2 Hz,1H), 7.30-7.24 (m, 1H), 7.23-7.18 (m, 1H), 5.15 (s, 2H), 4.48-4.34 (m,2H), 3.48 (s, 3H), 1.40 (t, J=7.2 Hz, 3H).

Step 3. To a mixture of A-4-2 (5.70 g, 22.25 mmol, 1.00 eq.) and(R)-2-methylpropane-2-sulfinamide (4.05 g, 33.38 mmol, 1.50 eq.) in THF(50.00 mL) was added Ti(OEt)₄ (7.61 g, 33.38 mmol, 1.50 eq.) in oneportion at ambient temperature under N₂. The mixture was heated to 70°C. and stirred for 12 hours. TLC showed the starting material wasconsumed completely. The mixture was cooled to ambient temperature andconcentrated in vacuum at 45° C. The residue was poured into water (100mL). The aqueous phase was extracted with ethyl acetate (300 mL×3). Thecombined organic phase was washed with brine (300 mL), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by silica gel chromatography (column height: 250 mm, diameter:100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=20/1,5/1) to afford A-4-3 (3.20 g, 8.90 mmol, 40.02% yield) as a yellow oil.¹HNMR (400 MHz, CHLOROFORM-d) δ 7.56 (dd, J=3.2, 8.2 Hz, 1H), 7.30-7.24(m, 1H), 7.23-7.18 (m, 1H), 5.15 (s, 2H), 4.48-4.34 (m, 2H), 3.48 (s,3H), 1.40 (t, J=7.2 Hz, 3H).

Step 4. To a solution of A-4-3 (3.00 g, 8.69 mmol, 1.00 eq.) in MeOH(30.00 mL) was added NaBH₄ (361.44 mg, 9.56 mmol, 1.10 eq.) portion-wiseat 0° C. under N₂. The reaction mixture was warmed to ambienttemperature for 2 hours. The reaction was quenched with ice-water (50mL) slowly and then extracted with DCM (100 mL×3). The combined organicphase was washed with brine (100 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=10/1 to 3:1) toafford A-4-4S (1.20 g, 4.98 mmol, 38% yield, first fraction) and A-4-4R(600 mg, 19%, second fraction) were obtained as an oil. ¹HNMR of A-4-4S(400 MHz, CHLOROFORM-d) δ 7.11 (dd, J=4.4, 9.0 Hz, 1H), 7.04 (dd, J=3.2,8.8 Hz, 1H), 7.00-6.93 (m, 1H), 5.33 (d, J=8.0 Hz, 1H), 5.18 (s, 2H),4.41 (d, J=8.0 Hz, 1H), 4.23-4.12 (m, 2H), 3.49 (s, 3H), 1.23-1.17 (m,12H). ¹HNMR of A-4-4R (400 MHz, CHLOROFORM-d) δ 7.12 (dd, J=4.4, 8.8 Hz,1H), 7.02-6.94 (m, 2H), 5.41 (d, J=4.0 Hz, 1H), 5.16 (s, 2H), 4.61 (d,J=4.0 Hz, 1H), 4.29-4.13 (m, 2H), 3.50 (s, 3H), 1.24-1.17 (m, 12H).

Step 5. To a solution of A-4-4S (600.00 mg, 1.66 mmol, 1.00 eq.) in THF(10.00 mL) was added MeMgBr (3 M in Et₂O, 4.43 mL, 8.00 eq.) drop-wiseat −78° C. under N₂. The mixture was stirred at ambient temperature for12 hr. The mixture was poured into saturated NH₄Cl (20 mL) and stirredfor 10 min. The aqueous phase was extracted with ethyl acetate (50 mL×3)and, the combined organic phase was washed with brine (50 mL), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum to affordA-4-5 (542.00 mg, 1.56 mmol, 93.97% yield) as yellow solid. ¹HNMR (400MHz, CHLOROFORM-d) δ 7.13 (dd, J=4.4, 9.0 Hz, 1H), 7.08-7.02 (m, 1H),6.96-6.89 (m, 1H), 5.24-5.15 (m, 2H), 4.67-4.35 (m, 2H), 3.50 (s, 3H),1.35 (s, 3H), 1.21 (s, 9H), 1.10 (s, 3H).

Step 6. Compound A-4-5 (540.00 mg, 1.55 mmol, 1.00 eq.) was dissolved inHCl/dioxane (4N, 5.00 mL) was stirred at ambient temperature under N₂for 2 hr. TLC showed the reaction complete. Methanol (20 mL) was addedto the mixture and stirred at ambient temperature for 10 min. Then thesolvent was removed under reduced pressure to give A-4-6 which was usedfor the next step without further purification.

Preparation of ethyl(S)-5-((1-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-2-methylpropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate(A-4)

A-4 was prepared with the general method A using A-4-6 in step 3.

Preparation of 2-(1-aminoeth-1-yl)-3-hydroxypyridine (A-6-3)

Step 1. To a solution of Compound A-6-1 (8.00 g, 58.33 mmol, 1.00 eq.)and potassium carbonate (24.19 g, 175.00 mmol, 3.00 eq.) in Methanol(50.00 mL) was added hydroxylamine hydrochloride (5.31 g, 75.83 mmol,1.30 eq.). The mixture was stirred at 25° C. for 12 hours. TLC(Petroleum ether/Ethyl acetate=1/1) showed the starting material wasconsumed completely and one new spot was found. The mixture was pourinto H₂O (100 mL) and extracted by ethyl acetate (100 mL*3). The organiclayer washed by brine (100 mL), dry over anhydrous sodium sulfate andconcentrated to give Compound A-6-2 (5.50 g, 36.15 mmol, 61.97% yield)as a yellow solid.

Step 2. To a solution of Compound A-6-2 (5.50 g, 36.15 mmol, 1.00 eq.)and zinc power (9.46 g, 144.59 mmol, 4.00 eq.) in ethanol (10.00 mL) wasadded ammonium chloride (11.15 g, 144.59 mmol, 4.00 eq.). The mixturewas stirred at 0-25° C. for 18 hours. TLC (Petroleum ether/Ethylacetate=1/1) showed the starting material was consumed completely andone new major spot was found. The mixture was filtered and the filtratewas concentrated to give Compound A-6-3 (4.00 g, 28.95 mmol, 80.08%yield) as a yellow solid. ¹HNMR: (400 MHz, DMSO-d6) δ: 7.75 (d, J=4.4Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.17 (dd, J=4.4, 8.0 Hz, 1H), 4.51 (q,J=6.4 Hz, 1H), 1.28 (d, J=6.4 Hz, 3H)

A-5 was prepared following the procedure for A-1 using2-(aminomethyl)-4-fluorophenol and ethyl5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate as starting material.

A-6 was prepared following the procedure for A-1 using A-6-3 and ethyl5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate as starting material.

Compd MS # Structure m/z ¹H NMR (400 MHz, CDCl₃) δ ppm A-1

345.2 9.10 (br. s., 1H), 8.18 (s, 1H), 8.08 (d, J = 7.5 Hz, 1H),6.88-6.83 (m, 2H), 6.81-6.73 (m, 1H), 6.05 (d, J = 7.5 Hz, 1H),5.63-5.52 (m, 2H), 4.44-4.28 (m, 2H), 1.54 (d, J = 6.4 Hz, 3H), 1.34 (t,J = 7.1 Hz, 3H) A-2

359.0 9.11 (br. s., 1H), 8.26 (s, 1H), 8.16 (d, J = 7.5 Hz, 1H), 6.96(dd, J = 5.1, 8.7 Hz, 1H), 6.91-6.81 (m, 2H), 6.18 (d, J = 7.5 Hz, 1H),5.73 (d, J = 8.5 Hz, 1H), 5.36 (q, J = 7.8 Hz, 1H), 4.51-4.38 (m, 2H),2.08-1.88 (m, 2H), 1.43 (t, J = 7.2 Hz, 3H), 0.97 (t, J = 7.3 Hz, 3H)A-3

375.1 8.23 (s, 1H), 8.16 (d, J = 7.5 Hz, 1H), 6.97-6.88 (m, 2H),6.87-6.81 (m, 1H), 6.28 (d, J = 7.8 Hz, 1H), 6.16 (d, J = 7.5 Hz, 1H),5.66 (br. s., 1H), 4.45- 4.34 (m, 2H), 3.86-3.65 (m, 2H), 3.47 (br. s.,1H), 2.29-2.19 (m, 1H), 2.15-2.07 (m, 1H), 1.39 (t, J = 7.0 Hz, 3H) A-4

389.2 8.30 (br. s., 1H), 8.22 (s, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.38(d, J = 7.2 Hz, 1H), 6.99 (dd, J = 5.2, 8.8 Hz, 1H), 6.86 (dt, J = 3.0,8.4 Hz, 1H), 6.40 (d, J = 8.4 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 5.40(d, J = 7.8 Hz, 1H), 4.47-4.36 (m, 2H), 1.51 (s, 3H), 1.41 (t, J = 7.0Hz, 3H), 1.23 (s, 3H) A-5

331.2 (300 MHz, DMSO-d6) δ ppm 9.61 (br. s., 1H), 8.52 (d, J = 7.2 Hz,1H), 8.28 (t, J = 5.4 Hz, 1H), 8.13 (s, 1H), 7.24 (d, J = 7.2 Hz, 1H),6.93-6.89 (m, 1H), 6.87-6.77 (m, 1H), 6.44 (d, J = 7.5 Hz, 1H), 4.51 (d,J = 5.4 Hz, 2H), 4.20 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H) A-6

328.2 (400 MHz, DMSO-d6) δ ppm 10.10 (br. s., 1H), 8.52 (d, J = 8.0 Hz,1H), 8.27 (d, J = 8.0 Hz, 1H), 8.14 (s, 1H), 8.05 (d, J = 3.6 Hz, 1H),7.27-7.13 (m, 2H), 6.64 (d, J = 8.0 Hz, 1H), 5.75 (t, J = 7.2 Hz, 1H),4.20 (q, J = 6.8 Hz, 2H), 1.45 (d, J = 6.4 Hz, 3H), 1.31 (d, J = 14.4Hz, 3H)

General Method B.

Preparation of(7S,13R)-7-ethyl-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one(1) and(6S,13R)-6-ethyl-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one(2)

Step 1: To a solution of (S)-2-ethyloxirane (1.00 g, 13.87 mmol) in H₂O(3.08 mL), MeOH (21.58 mL) and THF (3.08 mL) were added NaN₃ (4.51 g,69.35 mmol) and NH₄Cl (1.71 g, 31.90 mmol). The reaction mixture washeated at 75° C. for 4 hours, and then cooled to ambient temperaturefollowed by addition of water (100 mL). The mixture was extracted withethyl acetate (3×50 mL), and the combined extracts were washed withbrine (50 mL), dried over Na₂SO₄, and concentrated under reducedpressure. The crude product mixture of 1-1 and 2-1 was used in the nextstep without further purification.

Step 2. To a solution of 1-1 and 2-1 (1.35 g, 11.73 mmol) in THF (30.00mL) was added PPh₃ (4.61 g, 17.60 mmol), and the reaction solution wasstirred at ambient temperature for 65 hours. TLC demonstrated thecompletion of the conversion. To the reaction solution was added H₂O(3.00 g, 166.48 mmol), and the mixture was stirred for 7 hours followedby addition of a solution of Boc₂O (3.21 g, 14.72 mmol) andtriethylamine (2.38 g, 23.56 mmol) in THF (30 mL). The reaction wasstirred at ambient temperature for 19 hours, quenched by addition towater (50 mL), extracted with DCM (3×50 mL), dried with Na₂SO₄, andconcentrated under reduced pressure. Flash chromatography (ISCO system,silica (40 g), 0-35% ethyl acetate in hexane) provided the firstfraction of 1-2 (1.379 g, 61.86% yield). LC-MS m/z 212.2 (M+Na)⁺; ¹H NMR(500 MHz, DMSO-d6) δ ppm 6.62 (br t, J=5.73 Hz, 1H) 4.50 (d, J=5.16 Hz,1H) 3.34 (br s, 1H) 2.87-2.96 (m, 1H) 2.78-2.86 (m, 1H), 1.38-1.44 (m,1H) 1.37 (s, 9H) 1.15-1.26 (m, 1H) 0.84 (t, J=7.45 Hz, 3H). The secondfraction was a mixture of 1-2 and 2-2 (0.625 g, 28.03% yield).

Step 3. To a solution of 1-2 (467.00 mg, 2.47 mmol) and CH₃SO₂Cl (325.38mg, 2.84 mmol) in DCM (12.35 mL) at −20° C. was added Hunig's base(957.67 mg, 7.41 mmol). The reaction was warmed to ambient temperature,stirred for 22 hours, and then quenched by addition to water (50 mL).The mixture was extracted with DCM (3×50 mL), dried with Na₂SO₄ andconcentrated under reduced pressure. Flash chromatography (ISCO system,silica (24 g), 0-35% ethyl acetate in hexane) provided 1-3 (623.90 mg,2.33 mmol, 94.48% yield). LC-MS m/z 290.1 (M+Na)⁺.

Step 4. To a solution of 1-3 (116.46 mg, 0.436 mmol) and A-1 (120.00 mg,0.348 mmol) in DMF (1.74 mL) was added K₂CO₃ (240.82 mg, 1.74 mmol). Themixture was heated at 80° C. with stirring for 24 hours, cooled toambient temperature, diluted with DCM (3 mL), filtered through a syringefilter, and concentrated under reduced pressure. Flash chromatography(ISCO system, silica (12 g), 0-40% ethyl acetate in hexane) provided amixture of 1-4 and 2-4 (59.40 mg, 0.115 mmol, 33.06% yield). LC-MS m/z516.3 (M+H)⁺.

Step 5: To a solution of the mixture of 1-4 and 2-4 (59.40 mg, 0.115mmol) in MeOH (3.03 mL) and THF (1.49 mL) was added a solution of LiOHin H₂O (2M, 1.00 mL). The mixture was heated at 70° C. for 3 hours,cooled to ambient temperature, diluted with water and methanol, and thenquenched with aqueous HCl solution (2M, 1.00 mL) to acidic. The mixturewas extracted with DCM (3×5 mL), dried with Na₂SO₄ and concentratedunder reduced pressure. The residue was dried under high vacuumovernight, and then dissolved in DCM (4.0 mL) followed by addition ofHCl in 1,4-dioxane (4M, 2.0 mL) and stirring at ambient temperature for2 hours. The mixture was concentrated under reduced pressure, and driedunder high vacuum. The solid was dissolved in DMF (2 mL) and DCM (10 mL)and to the solution was added FDPP (50.76 mg, 0.132 mmol) and Hunig'sbase (74.23 mg, 0.574 mmol). The mixture was stirred for 2 hours, andthen quenched with aqueous Na₂CO₃ solution (2M, 12 mL). The mixture wasstirred for 5 min, and then extracted with DCM (4×10 mL). The combinedextracts were dried with Na₂SO₄ and concentrated under reduced pressure.Flash chromatography (ISCO system, silica (12 g), 0-10% methanol indichloromethane) followed by provided pure 1 (3.56 mg), 2 (3.83 mg), anda mixture of 1 and 2 (23.94 mg) with a total yield of 73.85%.

Compounds 3-8 were prepared using General Method B. In step 1,(R)-2-ethyloxirane was used for 3 and 4,(S)-2-((methoxymethoxy)methyl)oxirane for 5 and 6 followed by aciddeprotection of the acetal, and (R)-2-((methoxymethoxy)methyl)oxiranefor 7 and 8 followed by acid deprotection of the acetal.

General Method C.

Preparation of(7R,13R)-11-fluoro-7-(fluoromethyl)-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one(9)

To a solution of 5 (3.00 mg, 0.0081 mmol) in DCM (0.161 mL) was addedDeoxo-Fluor (3.58 mg, 0.0162 mmol). The mixture was stirred for 30 min,quenched with saturated NaHCO₃ solution (3 mL), extracted with DCM (3×3mL), dried with Na₂SO₄, and concentrated under reduced pressure. Flashchromatography (ISCO system, silica (12 g), 0-17.5% methanol indichloromethane) provided 9 (1.30 mg, 43.1% yield).

Compounds 10 and 11 were prepared using General Method C starting fromcompounds 7 and 8, respectively.

General Method D.

Preparation of(7R,13R)-7-[(dimethylamino)methyl]-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one(12)

Step 1. To a solution of 5 (11.00 mg, 0.0296 mmol) in DCM (0.60 mL) wasadded Dess-Martin Periodinane (25.13 mg, 0.0592 mmol). The mixture wasstirred at ambient temperature for 30 min, quenched with saturatedNaHCO₃ solution (3 mL), extracted with DCM:MeOH (5×3 mL, 1:1), driedwith Na₂SO₄, and concentrated under reduced pressure. Flashchromatography (ISCO system, silica (12 g), 0-22.5% methanol indichloromethane) of the residue provided the aldehyde 12-1 (8.10 mg,0.0219 mmol, 74.04% yield). LC-MS m/z 370.2 (M+H)⁺.

Step 2. To a solution of 12-1 (5.00 mg, 0.0135 mmol) in MeOH was addeddimethylamine (2 M, 0.034 mL). The mixture was heated at 60° C. for 2hrs, and cooled to ambient temperature followed by addition of sodiumborohydride (1.54 mg, 0.0406 mmol) and stirred for 1 h. Additionalportion of dimethylamine in THF (2M, 1 mL) and excess amount of NaBH4were added to drive the reaction to completion. The mixture was heatedat 45° C. overnight, and concentrated to dryness. The residue wasdissolved in MeOH and aqueous HCl (2M, 0.40 mL) was added. The mixturewas stirred for 30 min followed by addition of aqueous NaOH solution(2M, 0.45 mL), extracted with DCM (4×3 mL). The combined extracts weredried with Na₂SO₄ and concentrated under reduced pressure. Flashchromatography (0.060 mL TEA was added during compound loading] (ISCOsystem, silica (12 g), 0-25% methanol in dichloromethane) provided 12(1.89 mg, 0.0474 mmol, 35.03% yield) as a white solid.

General Method E.

Preparation of(6S,13R)-6-[(dimethylamino)methyl]-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one(13)

To a solution of 6 (7.20 mg, 0.0194 mmol) and CH₃SO₂Cl (8.88 mg, 0.0776mmol) in DCM (0.50 mL) at −20° C. was added Hunig's base (37.59 mg,0.291 mmol). The reaction was warmed to ambient temperature, stirred for1 hour, and then quenched by addition of saturated bicarbonate solution(2 mL). The mixture was extracted with DCM (3×3 mL), dried with Na₂SO₄,and concentrated under reduced pressure to dryness. A solution ofdimethylamine in THF (2 M, 1.98 mL) was added to the residue flask. Themixture was heated at 70° C. for 6 hours, and concentrated under reducedpressure. Flash chromatography (ISCO system, C18 (30 g gold col), 0-100%acetonitrile in water w/0.035% TFA) provided 13 as a TFA salt (2.93 mg).

General Method F.

Preparation of(7S,13R)-11-fluoro-N,13-dimethyl-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-7-carboxamide(14) and(7R,13R)-11-fluoro-N,13-dimethyl-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-7-carboxamide(15)

To a solution of 3-amino-2-hydroxypropanoic acid (3.50 g, 33.30 mmol,1.00 eq.) in 1,4-dioxane (30.00 mL) was added NaOH (1.33 g, 33.30 mmol,1.00 eq.) in H₂O (30.00 ml) drop-wise at 0° C. The mixture was stirredat 0° C. for 1 hr followed by addition of (Boc)₂O (8.29 g, 37.97 mmol,1.14 eq.). The mixture was warmed to ambient temperature and stirred for11 hours, quenched with addition of aqueous HCl solution (1M, 5 mL) at0° C. to adjust pH-6, and then extracted with EtOAc (20 mL×3). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure to3-((tert-butoxycarbonyl)amino)-2-hydroxypropanoic acid (3.50 g) whichwas used directly without further purification. ¹H NMR (400 MHz, CDCl₃)δ 7.93 (br. s., 1H), 5.41 (br. s., 1H), 4.32 (br. s., 1H), 3.65-3.40 (m,2H), 1.42 (s, 9H).

Step 2. To a solution of3-((tert-butoxycarbonyl)amino)-2-hydroxypropanoic acid (1.00 g, 4.87mmol, 1.00 eq.) in DCM (24.00 mL) and DMF (24.00 mL) was addedmethanamine (1.32 g, 19.49 mmol, 4.00 eq., HCl salt), EDCI (1.40 g, 7.31mmol, 1.50 eq.), HOBt (987 mg, 7.31 mmol, 1.50 eq.) and4-methylmorpholine (2.96 g, 29.24 mmol, 6.00 eq.). The mixture wasstirred at ambient temperature for 16 h, and then concentrated. Theresidue was diluted with citric acid (100 mL) and extracted withEtOAc(200 mL×2). The combined organic layers were washed with aqueoussaturated NaHCO₃ (100 mL), dried over MgSO₄, filtered and concentratedin vacuo to provide tert-butyl(2-hydroxy-3-(methylamino)-3-oxopropyl)carbamate (980.00 mg, 4.49 mmol,92.20% yield) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.03 (br. s.,1H), 5.41-5.14 (m, 2H), 4.19 (d, J=2.8 Hz, 1H), 3.65-3.55 (m, 1H),3.54-3.44 (m, 1H), 2.85 (d, J=5.2 Hz, 3H), 1.45 (s, 9H).

Step 3. To a stirred solution of tert-butyl(2-hydroxy-3-(methylamino)-3-oxopropyl)carbamate (980.00 mg, 4.49 mmol,1.00 eq.) in DCM (60.00 mL) was added TEA (2.27 g, 22.45 mmol, 5.00eq.), 4-methylbenzenesulfonyl chloride (1.71 g, 8.98 mmol, 2.00 eq.) andcatalytic amount DMAP (54.86 mg, 449.03 μmol, 0.10 eq.) at 0° C. for 15min. The reaction was stirred at ambient temperature for 12 h, quenchedby addition of citric acid (100 mL), then diluted with EtOAc (100 mL),and extracted with EtOAc(100 mL×3). The combined organic layers werewashed with saturated NaHCO₃ (100 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography (SiO2, Petroleum ether/Ethylacetate=10/1 to 1:1) to provide 14-1 (1.05 g, 2.82 mmol, 62.80% yield)as a white solid. ¹H NMR (CDCl₃, 400 MHz) 7.84 (d, J=8.0 Hz, 1H), 7.39(d, J=8.0 Hz, 1H), 6.38 (br. s., 1H), 4.87 (t, J=4.8 Hz, 1H), 4.77 (br.s., 1H), 3.62-3.40 (m, 2H), 2.80 (d, J=4.8 Hz, 3H), 2.47 (s, 3H), 1.41(s, 9H).

Step 4. To a solution of A-1 (75.00 mg, 0.218 mmol) and 14-1 (89.23 mg,0.240 mmol) in DMF (1.1 mL) was added K₂CO₃ (150.52 mg, 1.09 mmol). Themixture was heated to 70° C. with stirring for 75 hour with the additionof more K₂CO₃ and 14-1 each day to drive the reaction to completion. Thereaction was cooled to ambient temperature, diluted with DCM (3 mL),filtered through a syringe filter, and concentrated under reducedpressure. Flash chromatography (ISCO system, silica (12 g), 0-100% ethylacetate in hexane) provided 14-2 (65.00 mg, 0.119 mmol, 54.8% yield).LC-MS m/z 545.3 (M+H)⁺.

Step 5. To a solution of 14-2 (65.00 mg, 0.119 mmol) in MeOH (2.98 mL)and THF (2.01 mL) at ambient temperature was added aqueous LiOH solution(2.0 M, 2.01 mL). The mixture was heated at 70° C. for 2 hours, cooledto ambient temperature, diluted with water and methanol, and thenquenched with aqueous HCl solution (2.0 M2.01 mL) to acidic. The mixturewas extracted with DCM (3×5 mL), dried with Na₂SO₄, concentrated underreduced pressure, and dried under high vacuum overnight. To the residuewas added DCM (3.00 mL) followed by addition of HCl in 1,4-dioxane (4 M,2.00 mL). The mixture was stirred ambient temperature for 1.5 hour,concentrated under reduced pressure, and dried under high vacuum. To theresidue was added DMF (4.00 mL) and FDPP (50.34 mg, 0.131 mmol) followedby the addition of Hunig's base (76.97 mg, 0.596 mmol). The mixture wasstirred at ambient temperature for 1.5 hour, quenched with aqueousNa₂CO₃ solution (2M, 4.0 mL), and stirred for 5 min. The mixture wasextracted with DCM (4×10 mL), and the combined extracts were dried withNa₂SO₄ and concentrated under reduced pressure. Flash chromatography(ISCO system, silica (12 g), 0-17.5% methanol in dichloromethane)provided pure 14 (2.29 mg) as the first fraction and 15 (3.63 mg) as thelast fraction. The middle fraction (12.8 mg) was a mixture of 14 and 15.

General Method G.

Preparation of(6R,13R)-6-(difluoromethyl)-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one(16),(6S,13R)-6-(difluoromethyl)-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one(17), and(7R,13R)-7-(difluoromethyl)-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one(18)

Step 1. To a solution of 3-amino-1,1-difluoropropan-2-ol hydrochloridesalt (150.29 mg, 1.16 mmol) and Boc-anhydride (316.46 mg, 1.45 mmol) inTHF (5.8 mL) was added Hunig's base (449.76 mg, 3.48 mmol). The mixturewas stirred for 18 hours, and concentrated under reduced pressure. Flashchromatography (ISCO system, silica (12 g), 0-40% ethyl acetate inhexane) provided tert-butyl (3,3-difluoro-2-hydroxypropyl)carbamate(195.20 mg, 0.924 mmol, 79.8% yield).

Step 2. To a solution of tert-butyl(3,3-difluoro-2-hydroxypropyl)carbamate (195.20 mg, 0.924 mmol), TosCl(211.44 mg, 1.11 mmol), and DMAP (5.65 mg, 0.462 mmol) in DCM (4.6 mL)at −78° C. was added Hunig's base (358.33 mg, 2.77 mmol). The reactionwas warmed to ambient temperature, stirred for 15 hours, and thenquenched by addition to water (15 mL). The mixture was extracted withDCM (3×10 mL), dried with Na₂SO₄ and concentrated under reducedpressure. Flash chromatography (ISCO system, silica (12 g), 0-25% ethylacetate in hexane) provided3-[(tert-butoxycarbonyl)amino]-1,1-difluoropropan-2-yl4-methylbenzenesulfonate (240.60 mg, 0.658 mmol, 71.25% yield).

Step 3. To a solution of A-1 (75.00 mg, 0.218 mmol) and3-[(tert-butoxycarbonyl)amino]-1,1-difluoropropan-2-yl4-methylbenzenesulfonate (95.50 mg, 0.261 mmol) in DMF (1.09 mL) wasadded K₂CO₃ (150.52 mg, 1.09 mmol). The mixture was heated at 80° C.with stirring for 18 hours, cooled to ambient temperature, diluted withDCM (3 mL), filtered through a syringe filter, and concentrated underreduced pressure. Flash chromatography (ISCO system, silica (12 g),0-50% ethyl acetate in hexane) provided the first fraction which wasidentified as 16-1 (26.00 mg, 0.0484 mmol, 22.21% yield), and the secondfraction as a mixture of 17-1 and 18-1 (26.7 mg).

Step 4. 16-1 was converted to 16 using the method of Step 5 in GeneralMethod B. The mixture of 17-1 and 18-1 were converted to a mixture ofmacrocyclic compounds which was separated with flash chromatography(ISCO system, silica (12 g), 0-7.5% methanol in dichloromethane) toprovide 17 and 18.

Compounds 19 and 22-24 were prepared according to General Method F usingt-butyl (2-chloroethyl)carbamate in the place of 14-1 and A-2-A-4 inStep 1.

Compounds 20 and 21 were prepared according to General Method B usingA-2 in the place of A-1 in Step 4.

Compound 25 were prepared according to General Method B using(2R)-2-(methoxymethyl)oxirane in the place of 2-ethyloxirane in Step 1.

General Method H.

Preparation of(7S,13R)-11-fluoro-7-methyl-13-(²H₃)methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one(26)

Step 1. To a mixture of 26-1 (10.00 g, 71.37 mmol, 1.00 eq.) and(R)-2-methylpropane-2-sulfinamide (8.65 g, 71.37 mmol, 1.00 eq.) in DCM(500.00 mL) was added cesium carbonate (69.76 g, 214.11 mmol, 3.00 eq.)in one portion at 20° C. under N₂ and then stirred at 50° C. for 12 hr.The mixture was cooled to 20° C. and concentrated in reduced pressure at45° C. The residue was poured into water (300 mL). The aqueous phase wasextracted with ethyl acetate (500 mL×3), combined organic phase andwashed with saturated brine (500 mL), dried over anhydrous sodiumsulfate, filtered and concentrated in vacuum to give a residue whichtriturated by petroleum ether to give 26-2 (15.00 g, 61.65 mmol, 86.38%yield) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ 10.85 (s, 1H), 8.64(s, 1H), 7.21-7.14 (m, 2H), 6.99 (dd, J=4.4, 10.0 Hz, 1H), 1.27 (s, 9H).

Step 2. To a mixture of tert-butyl (R)-(2-hydroxypropyl)carbamate (5.00g, 28.54 mmol, 1.20 eq.) and 26-2 (5.79 g, 23.78 mmol, 1.00 eq.) intoluene/THF (15 mL, v/v=1:1) was added PPh₃ (7.49 g, 28.54 mmol, 1.20eq.). The reaction mixture was cooled to about 0° C., and DIAD (5.77 g,28.54 mmol, 5.55 mL, 1.20 eq.) was added drop-wise for 10 min. Themixture was allowed warm to 25° C., and after stirring for about tenminutes, an additional 15 ml of toluene and 15 ml of THF were added tothe thick orange solution. The mixture was stirred at 25° C. for anadditional 24 hours, The reaction mixture was concentrated in vacuum andthe residue was purified by column chromatography (Petroleum ether:Ethylacetate=20/1 to 5/1) to give 26-3 (11.00 g, 19.23 mmol, 80.84% yield,70% purity) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ 8.95 (s, 1H),7.65 (dd, J=2.8, 8.8 Hz, 1H), 7.21-7.10 (m, 1H), 7.00 (br dd, J=4.0, 8.8Hz, 1H), 5.08 (br s, 1H), 4.57 (br s, 1H), 3.45 (br s, 1H), 3.36-3.22(m, 1H), 1.43 (s, 9H), 1.30 (br d, J=6.4 Hz, 3H), 1.25 (br s, 9H)

Step 3. CD₃MgI (1 M, 22.5 mL) was added to a solution of 26-3 (3.00 g,7.49 mmol) and MgBr₂.Et₂O (12.7 g, 45 mmol) in MeTHF (37.5 mL) at −10°C. Reaction was slowly warmed to 0° C. over 3 hours then quenched byaddition to saturated NH₄Cl solution (50 mL).

The mixture was extracted with DCM (3×50 mL), dried with Na₂SO₄ andconcentrated under reduced pressure. Flash chromatography (ISCO system,silica (40 g), 0-50% ethyl acetate in hexane) provide 26-4 (1.72 g, 4.10mmol, 54% yield) and 26-5 (970 mg, 2.31 mmol, 30% yield).

Step 2. I₂ (117 mg, 46 μmol) was added to 26-5 (970 mg, 2.31 mmol) inTHF (9.96 mL) and water (2.04 mL). The reaction was heated to 50° C. for6 hours, concentrated under reduced pressure, and dried under highvacuum to obtain crude 26-6.

Step 3. To a solution of crude 26-6 and ethyl5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (521 mg, 2.31 mmol) inEtOH (12 mL) was added Hunig's base (750 mg, 5.8 mmol). The mixture washeated to 60° C. with stirring for 20 hours. The reaction was cooled toambient temperature, quenched by addition to saturate NaHCO₃ solution(25 mL) and water (75 mL) and extracted with DCM (3×50 mL). The combinedextracts were dried with Na₂SO₄ and concentrated under reduced pressure.Flash chromatography (ISCO system, silica (40 g), 0-40% ethyl acetate inhexane) provided 26-7 (894 mg, 1.77 mmol, 76% yield over 2 steps). LC-MSm/z 505.3 (M+H)⁺.

Step 4. To a solution of 26-7 (894 mg, 1.77 mmol) in MeOH (40 mL) andTHF (10 mL) at ambient temperature was added aqueous LiOH solution (2.0M, 15 mL). The mixture was heated at 70° C. for 22 hours, cooled to −20°C. then quenched with aqueous HCl solution (2.0 M, 15.1 mL) to acidic.The mixture was extracted with DCM (3×50 mL), dried with Na₂SO₄,concentrated under reduced pressure, and dried under high vacuumovernight. To the residue was added DCM (30 mL) followed by addition ofHCl in ether (2 M, 10 mL). The mixture was stirred at ambienttemperature for 20 hours, concentrated under reduced pressure, and driedunder high vacuum. To a solution of DMF (20 mL), DCM (100 mL) andHünig's base (3.71 g, 28.70 mmol) was added 1/3 of this crude materialthen 1/3 of FDPP (603.21 mg, 1.57 mmol) and them mixture stirred for 1hour. The additions were preformed 2 more times and the final mixturewas stirred at ambient temperature for 18 hours, quenched with aqueousNa₂CO₃ solution (2M, 100 mL), and stirred for 5 min. The mixture wasextracted with DCM (3×50 mL), and the combined extracts were dried withNa₂SO₄ and concentrated under reduced pressure. Flash chromatography(ISCO system, silica (40 g), 0-8.75% methanol in dichloromethane)provided 26 (446 mg, 79% yield).

General Method I.

Preparation of7-methyl-6,7,14,15-tetrahydro-2H-3,5-(azenometheno)pyrrolo[3,4-f][1,4,8,10]benzoxatriazacyclotridecin-16(13H)-one(33)

Step 1. Triethylamine (1.10 g, 10.9 mmol) was added to a solution of2-(1-aminoethyl)phenol (499 mg, 3.64 mmol) and trifluoroacetic anhydride(841 mg, 4.0 mmol) in DCM (18.2 mL) at 0° C. Reaction was stirred for 2hours at 0° C. then quenched by adding to 0.5 M HCl (100 mL). Themixture was extracted with DCM (150 mL). The extracts was washed with0.5 M HCl (3×100 mL), dried with Na₂SO₄, and concentrated under reducedpressure. The residue was dried under high vacuum to obtain 33-1 (809.3mg, 3.47 mmol, 95% yield).

Step 2. 33-1 (550 mg, 2.36 mmol) and tert-butyl(2-hydroxyethyl)carbamate (760 mg, 4.72 mmol) were mixed together andazeotrope dried from DCM:Toluene. The dried mixture was re-dissolved inDCM (1.50 mL) and PPh3 (1.27 g, 4.84 mmol) was added to the solution.The mixture was stirred till everything was completely dissolved. Thesolution was cooled to 0° C. and DIAD (1.03 g, 5.07 mmol) was added veryslowly under stirring. The reaction was warmed to room temperature andstirred for 13 hours. The reaction was quenched by pouring to water (100mL), and extracted with DCM (3×75 mL). The combined extracts were driedwith Na₂SO₄ and concentrated under reduced pressure. Flashchromatography (ISCO system, silica (24 g), 5-20% ethyl acetate inhexane) provided 33-2 (655 mg, 1.74 mmol, 74% yield).

Step 3. To a solution of 33-2 (421 mg, 1.12 mmol) in MeOH (4.80 mL) andH2O (1.20 mL) was added K₂CO₃ (309 mg, 2.24 mmol) at room temperature.The reaction was heated to 60° C. for 2.5 hours, then cooled and pouredinto 0.4 M NaOH solution (50 mL), and extracted with DCM (3×50 mL). Thecombined extracts were dried with Na₂SO₄, and concentrated under reducedpressure. The residue was dried under high vacuum to obtain 33-3 (227.8mg, 812 μmol, 72% yield).

Step 4. To a mixture of NaH (28 mg, 1.18 mmol) in DMF (4.06 mL) wasadded 33-4 (200 mg, 812 μmol) at 0° C. The mixture was stirred for 30min followed by addition of SEMCl (176 mg, 1.06 mmol). The reaction waswarmed to room temp and stirred for 2.5 hours, then quenched by additionto water (25 mL). The mixture was extracted with DCM (3×15 mL), and thecombined extracts were dried with Na₂SO₄ and concentrated under reducedpressure. Flash chromatography (ISCO system, silica (12 g), 0-50% ethylacetate in hexane) provide 33-5 (261.9 mg, 696 μmol, 86% yield).

Step 5. To a degassed solution of 33-3 (75 mg, 267 μmol), 33-5 (103 mg,267 μmol), N,N-dimethylglycine (8.3 mg, 80 μmol) and K₂CO₃ (92 mg, 668μmol) in DMSO (1.34 mL) was added CuI (7.6 mg, 40 μmol). The reactionwas heated to 100° C. for 4.5 hours, poured into water (25 mL), andextracted with DCM (3×15 mL). The combined extracts were dried withNa₂SO₄ and concentrated under reduced pressure. Flash chromatography(ISCO system, silica (12 g), 0-40% ethyl acetate in hexane) provided33-6 (30.2 mg, 51.5 μmol, 19% yield).

Step 6. To a solution of 33-6 (30.2 mg, 51.5 μmol) in MeOH (3 mL) andTHF (1 mL) at ambient temperature was added aqueous LiOH solution (2.0M, 1 mL). The mixture was heated at 70° C. for 45 minutes, cooled to−20° C. then quenched with aqueous HCl solution (2.0 M, 1.1 mL) toacidic. The mixture was extracted with DCM (3×5 mL), dried with Na₂SO₄,concentrated under reduced pressure, and dried under high vacuum. Thecrude material was dissolved in DCM (4 mL) followed by addition of HClin ether (2 M, 2 mL). The mixture was stirred ambient temperature for 2hours, concentrated under reduced pressure, and dried under high vacuum.The crude material was dissolved in in DMF (1.0 mL) and DCM (4.0 mL) andHünig's base (33 mg, 256 μmol) then FDPP (20.7 mg, 54 μmol) was added inone portion. The reaction was stirred for 4 hours then quenched with 2 MNa₂CO₃ solution (5 mL). Mixture was stirred for 5 min then extractedwith DCM (4×10 mL). Combined extracts were dried with Na₂SO₄ andconcentrated under reduced pressure. Flash chromatography (ISCO system,silica (12 g), 0-100% ethyl acetate in hexane) provided 33-7 (13.9 mg,30.6 μmol, 59% yield).

Step 7. 33-7 (13.9 mg, 30.6 μmol) was dissolved in DCM (1.00 mL) and TFA(1.00 mL). The mixture was stirred for 30 min until all startingmaterial was consumed. The reaction solution was concentrated to drynessunder reduced pressure and azeotrope dried with toluene (1 mL). Theresidue was re-dissolved in DCM (1.00 mL) and MeOH (0.5 mL) and NH₄OH(18 M, 150 μL) was added. The solution was stirred for 15 minutes, andconcentrated under reduced pressure. Flash chromatography (ISCO system,silica (12 g), 0-15% methanol in dichloromethane) provided 33 (4.9 mg,15 μmol, 49% yield).

General Method J.

Preparation of[(7S,13R)-11-fluoro-7-methyl-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-13-yl]acetonitrile(38)

Step 1. To a solution of Zn (3.02 g, 46.24 mmol, 3.75 eq.) and2-bromoacetonitrile (3.70 g, 30.83 mmol, 2.50 eq.) in THF (20.00 mL) wasadded TMSCl (254.52 mg, 2.34 mmol, 0.19 eq.) dropwised under N₂. Themixture was stirred at 0° C. to 20° C. for 2 hr. Then A-1-3 (3.00 g,12.33 mmol, 1.00 eq.) was added to the mixture and the mixture wasstirred at 50° C. for 12 hr. The TLC (PE:EtOAc=1:2) showed the reactionworked well. Then the mixture was quenched by water (20 mL) andextracted with EtOAc (50 mL*5), the organic layer washed by brine (50mL), dried over Na₂SO₄. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=10/1 to 1:5) to give38-1 (260 mg, PE:EtOAc=1:2, Rf=0.5) and 38-2 (441 mg, PE:EtOAc=1:2,Rf=0.4) as white solid. ¹H NMR (400 MHz, CDCl₃, 38-1) δ 9.60 (s, 1H),6.78 (dd, J=3.0, 8.3 Hz, 1H), 6.49 (dt, J=3.1, 8.5 Hz, 1H), 6.17 (dd,J=4.6, 8.9 Hz, 1H), 5.62 (d, J=10.2 Hz, 1H), 4.45 (dt, J=4.6, 10.3 Hz,1H), 3.12 (dd, J=10.5, 17.0 Hz, 1H), 2.65 (dd, J=4.7, 17.0 Hz, 1H), 1.38(s, 9H); ¹H NMR (400 MHz, CDCl₃, 38-2) δ 9.10 (br. s., 1H), 6.92 (dq,J=3.0, 8.7 Hz, 2H), 6.81 (dd, J=4.6, 8.7 Hz, 1H), 4.83-4.71 (m, 2H),3.11-3.02 (m, 2H), 1.31 (s, 9H).

Step 2. 38-1 (100.00 mg, 351.68 μmol) and tert-butyl(R)-(2-hydroxypropyl)carbamate (123.25 mg, 703.36 μmol) were mixedtogether and azetrope dried from DCM:Toluene. The mixture wasredissolved in DCM (200.00 μL) and PPh₃ (189.10 mg, 720.94 μmol) wasadded to the solution. The mixture was stirred till everythingcompletely dissolved and then cooled to 0° C. To the solution was addedDIAD (145.78 mg, 720.94 μmol, 141.53 μL) very slowly with mixing. Thereaction was warmed to room temperature, stirred for 19 hour, quenchedby addition to water (4 solvent volume), and extracted with DCM (3×3mL). The combined extracts were dried with Na₂SO₄ and concentrated underreduced pressure. Flash chromatography (ISCO system, silica (12 g),0-100% ethyl acetate in hexane) to provide 38-3 (58.8 mg, 37% yield).

38-3 was converted to 38 following the reaction steps 2-4 in GeneralMethod H.

General Method K

Preparation of tert-butyl((S)-2-(2-((R)-1-aminoethyl)-4-fluorophenoxy)-propyl)carbamate (40-5)

Step 1. To a solution of 40-1 (500.00 g, 3.24 mol, 1.00 eq.), tert-butyl(R)-(2-hydroxypropyl)carbamate (851.57 g, 4.86 mol, 1.50 eq.) and PPh₃(1.27 kg, 4.86 mol, 1.50 eq.) in dichloromethane (1.5 L) was added DEAD(902.79 g, 5.18 mol, 940.41 mL, 1.60 eq.) drop-wise at 0° C. Thesolution was stirred at 25° C. for 4 hours. TLC indicated one major newspot with larger polarity was detected, and the starting material wasconsumed completely. Petroleum ether (1.5 L) was added to the mixture,then filtrated the solid, the solvent of the filtrate was removed andthe residue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=20/1 to 10:1) to give 40-2 (680.00 g, 2.18 mol,67.28% yield) as a red oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.38 (dd,J=3.2, 8.8 Hz, 1H), 7.13 (ddd, J=3.2, 7.2, 8.8 Hz, 1H), 6.97 (dd, J=4.0,8.8 Hz, 1H), 5.06 (br. s., 1H), 4.63-4.52 (m, 1H), 3.52-3.39 (m, 1H),3.38-3.27 (m, 1H), 2.59 (s, 3H), 1.42 (s, 9H), 1.32 (d, J=6.4 Hz, 3H).

Step 2. To a mixture of (R)-2-methylpropane-2-sulfinamide (219.98 g,1.82 mol, 1.50 eq.), diglyme (162.35 g, 1.21 mol, 172.71 mL, 1.00 eq.)and 40-2 (376.00 g, 1.21 mol, 1.00 eq.) in THF (1.88 L) and2-methyltetrahydrofuran (1.88 L) was added tetraethoxytitanium (552.03g, 2.42 mol, 501.85 mL, 2.00 eq.) in one portion at 20° C. under N₂. Themixture was stirred at 60° C. for 12 hr. TLC showed about 15% startingmaterial remaining. The mixture was cooled to 20° C. Water (2 L) wasadded. The aqueous phase was extracted with ethyl acetate (2000 mL×3).The combined organic phase was washed with saturated brine (1 L), driedover anhydrous Na₂SO₄, filtered and concentrated in vacuum to give a40-3 (520.00 g, crude) as a red oil which used for the next step withoutfurther purification.

Step 3. To a solution of 40-3 (520.00 g, 1.25 mol, 1.00 eq.) in THF/H₂O(3.82 L/78 mL) was added NaBH₄ (142.37 g, 3.76 mol, 3.00 eq.) at −50°C., the reaction was warmed to 25° C., and then stirred at 25° C. for 12hr. TLC showed starting material was completely consumed. Water (1 L)was added to the mixture and extracted with EtOAc (2 L×2). The organiclayer was washed with saturated NaCl (1 L) and dried over Na₂SO₄.Removed the solvent and the residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=20/1 to 10:1) togive 40-4 (270.00 g, 570.40 mmol, 45.47% yield). ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.06 (dd, J=3.2, 9.2 Hz, 1H), 6.95 (dt, J=3.2, 8.4 Hz,1H), 6.80 (dd, J=4.4, 9.2 Hz, 1H), 6.70 (br. s., 1H), 4.93 (d, J=6.0 Hz,1H), 4.57-4.46 (m, 1H), 3.68-3.65 (m, 1H), 3.59-3.57 (m, 1H), 3.22-3.10(m, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.40 (s, 9H), 1.27-1.25 (m, 3H), 1.22(s, 9H).

Step 4. To a solution of 40-4 (270.00 g, 570.40 mmol, 1.00 eq.) andmolecular iodine (28.95 g, 114.08 mmol, 22.98 mL, 0.20 eq.) in THF (2.16L) was added H₂O (540.00 mL) at 25° C. under N₂. The mixture was stirredat 50° C. for 3 hours. TLC showed the starting material was consumedcompletely. The mixture was concentrated to give 40-5 (330.00 g, crude)as a white solid. LCMS: m/z 313.2 (M+H+). ¹H NMR (400 MHz, CHLOROFORM-d)δ 7.08 (dd, J=2.8, 9.4 Hz, 1H), 6.91-6.79 (m, 2H), 5.72 (br. s., 1H),4.55-4.32 (m, 2H), 3.52-3.41 (m, 1H), 3.31-3.19 (m, 1H), 1.42 (s, 9H),1.38 (d, J=6.8 Hz, 3H), 1.29 (d, J=6.0 Hz, 3H).

General Method L.

Preparation of(3aR,9R,17aS)-7-fluoro-9-methyl-1,2,3,3a,9,10,17,17a-octahydro-16H-11,13-ethenocyclopenta[b]pyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-16-one(41)

Step 1. To a solution of (1S,2S)-2-aminocyclopentan-1-ol (41-1) HCl salt(500.00 mg, 3.63 mmol) and triethylamine (1.10 g, 10.89 mmol, 1.51 mL)in MeOH (18.15 mL) was added Boc₂O (1.58 g, 7.26 mmol). The reaction wasstirred for 22 hour, concentrated under reduced pressure. Flashchromatography (ISCO system, silica (24 g), 0-50% ethyl acetate inhexane) provide 41-2 (714.2 mg, 3.55 mmol, 97.76% yield).

Step 2. 41-2 (100.00 mg, 496.87 μmol) and A-1 (171.09 mg, 496.87 μmol)were mixed together and azetrope dried from DCM:Toluene. The mixture wasredissolved in DCM (248.43 μL) and PPh₃ (136.84 mg, 521.71 μmol) wasadded to the solution. The mixture was stirred till everythingcompletely dissolved. DIAD (105.50 mg, 521.71 μmol, 102.43 μL) was addedvery slowly with mixing. The reaction was stirred for 16 hour, thenquenched by addition to water (4 mL), and extracted with DCM (3×3 mL).The combined extracts were dried with Na₂SO₄ and concentrated underreduced pressure. Flash chromatography (ISCO system, silica (12 g),0-50% ethyl acetate in hexane) to provide 41-3 (17.6 mg, 6.7% yield).

Step 3. 41-3 was converted to 41 following the step 4 in General methodH.

General Method M.

Preparation of(7R,13R)-7-ethyl-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-4(5H)-one(58)

Step 1: MeMgBr (3 M, 6.45 mL) in Et₂O was added to a solution of 58-1(1.00 g, 6.45 mmol) in THF (32 mL) at −78° C. The reaction was slowlywarmed to 5° C. over 4 hours, and then cooled back down to −78° C., andquenched by addition of saturated aqueous NH₄Cl solution (20 mL). Themixture was warmed to room temperature and extracted with DCM (3×10 mL).The combined extracts were dried with Na₂SO₄ and concentrated underreduced pressure. Flash chromatography (ISCO system, silica (24 g),0-50% ethyl acetate in hexane) provided 58-2 (1.10 g, 6.43 mmol, 100%yield).

Step 2: DMSO (753 mg, 9.65 mmol, 685 μL) in DCM (5 mL) was addeddropwise to oxalyl chloride (1.22 g, 9.65 mmol, 827 μL) in DCM (15 mL)at −78° C. The solution was stir for 20 min, and then 58-2 (1.10 g, 6.43mmol) in DCM (8 mL) was added dropwise. The reaction was stirred for 20min and then TEA (3.25 g, 32 mmol, 4.46 mL) was added dropwise. Thereaction was slowly warmed to room temperature, stirred for 2.5 hours,and quenched by addition to water (100 mL). The mixture was extractedwith DCM (3×25 mL), and the combined extracts were dried with Na₂SO₄ andconcentrated under reduced pressure. Flash chromatography (ISCO system,silica (24 g), 0-40% ethyl acetate in hexane) provided 58-3 (1.01 g,5.97 mmol, 92% yield).

Step 3: To a solution of 58-3 (1.01 g, 5.97 mmol),(S)-2-methylpropane-2-sulfinamide (1.00 g, 8.25 mmol) and diglyme (801mg, 5.97 mmol, 852 μL) in THF (6.0 mL) and MeTHF (6.0 mL) was addedTi(OEt)₄ (2.59 g, 11.34 mmol, 2.37 mL). The mixture was heated at 60° C.for 4 hours, cooled to room temperature, and quenched by addition towater (100 mL). The mixture was extracted with DCM (3×50 mL), and theextracts were dried with Na₂SO₄ and concentrated under reduced pressure.Flash chromatography (ISCO system, silica (24 g), 5-30% ethyl acetate inhexane) provided 58-4 (1.31 g, 4.81 mmol, 80% yield).

Step 4: Added NaBH₄ (546 mg, 14.4 mmol) to 58-4 (1.31 g, 4.81 mmol) andH₂O (260 mg, 14.43 mmol, 260 μL) in THF (24 mL) at −78° C. Allowedreaction to slowly warm to room temperature, and stirred for 18 hours.Cooled reaction back down to −78° C. and quenched reaction with MeOH (3mL) then water (5 mL) then adjusted pH till neutral with 2 M HCl furtherdilute with water (75 mL) and extracted with DCM (3×75 mL). Combinedextracts were dried with Na₂SO₄ and concentrated under reduced pressure.Flash chromatography (ISCO system, silica (40 g), 30-60% ethyl acetatein hexane) provided 56-5 (758.1 mg, 2.76 mmol, 57% yield) and 58-6(414.9 mg, 1.51 mmol, 31% yield).

Step 5: To a solution of 58-5 (757 mg, 2.76 mmol) in THF (11.5 mL) andH₂O (2.30 mL) was added I₂ (140 mg, 552 μmol). The mixture was heated at50° C. for 9 hours, and then concentrated under reduced pressure to give58-7. Compound was dried on high vacuum and used as is.

Step 6: To a solution of 58-7 (469.7 mg, 2.76 mmol) and5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (778 mg, 3.45 mmol) inEtOH (14.0 mL) was added Hünig's base (2.96 g, 22.9 mmol, 4.0 mL). Thesolution was heated at 80° C. for 64 hours. The mixture was concentratedunder reduced pressure. Flash chromatography (ISCO system, silica (40g), 50-100% ethyl acetate in hexane) provided 58-8 (871.4 mg, 2.42 mmol,87% yield).

Step 7: To 58-8 (869.65 mg, 2.42 mmol) in EtOH (15.0 mL) was added HClin 1,4-dioxane (4 M, 15.0 mL). The mixture was heated to 75° C., stirredfor 6 hours and concentrated under reduced pressure. Flashchromatography [loaded with DCM containing Et₃N (200 μL)] (ISCO system,silica (24 g), 0-10% methanol in dichloromethane) provide 58-9 (736.1mg, 2.13 mmol, 88% yield).

Step 8: 58-9 (100 mg, 289 μmol) and (S)-tert-butyl(2-hydroxybutyl)carbamate (68.5 mg, 362 μmol) were mixed together andazeotrope dried from DCM:Toluene. The residue was re-dissolved in DCM(150 μL) and PPh₃ (99 mg, 376 μmol) was added to the solution. Themixture was stirred till everything completely dissolved, and DIAD (76mg, 376 μmol, 73.9 μL) was added very slowly with mixing. The mixturewas heated at 35° C. for 2 hours, cooled to room temperature, andstirred for 3 days. The reaction was quenched by addition to water (4mL) and extracted with DCM (3×4 mL). The combined extracts were driedwith Na₂SO₄ and concentrated under reduced pressure. Flashchromatography (ISCO system, silica (12 g), 0-60% ethyl acetate inhexane) provided 58-10 (105.8 mg, 204 μmol, 70% yield).

Step 9. To a solution of 58-10 (105.8 mg, 204 μmol) in MeOH (4 mL) andTHF (1.5 mL) at ambient temperature was added aqueous LiOH solution (2.0M, 1.5 mL). The mixture was heated at 70° C. for 3 hours, cooled to −20°C. then quenched with aqueous HCl solution (2.0 M, 1.6 mL) to acidic.The mixture was extracted with DCM (3×5 mL), dried with Na₂SO₄,concentrated under reduced pressure, and dried under high vacuum. Thecrude material was dissolved in DCM (4 mL) followed by addition of HClin 1,4-dioxane (4 M, 3 mL). The mixture was stirred ambient temperaturefor 15 hours, concentrated under reduced pressure, and dried under highvacuum. The crude material was dissolved in in DMF (2.0 mL) and DCM (8.0mL) and Hünig's base (264 mg, 2.05 mmol, 357 μL) then FDPP (98 mg, 255μmol) was added in one portion. The reaction was stirred for 3 hoursthen quenched with 2 M Na₂CO₃ solution (5 mL). Mixture was stirred for 5min then extracted with DCM (3×10 mL). Combined extracts were dried withNa₂SO₄ and concentrated under reduced pressure. Flash chromatography(ISCO system, silica (12 g), 0-10% methanol in dichloromethane) provided58 (49.3 mg, 133 μmol, 65% yield).

General Method N.

Preparation of(7S)-11-fluoro-N,7-dimethyl-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-13-carboxamide(61)

Step 1. The HCl salt of 61-1 (250.42 mg, 1.13 mmol) and ethyl5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (254.96 mg, 1.13 mmol)were combined in ethanol (5.65 mL) and Hunig's base (1.46 g, 11.30 mmol,1.97 mL) was added. The mixture was stirred and warmed to 80° C. Thereaction was checked after 3 hours and was complete by LC-MS. Thereaction was cooled and worked up with water and ethyl acetate. Theaqueous layer was extracted twice more with ethyl acetate. The combinedorganic layer was washed with brine, dried over sodium sulfate,filtered. The crude was purified by column chromatography (DCM/methanol)to provide 61-2 (176 mg). Additional 61-2 (130 mg) was obtained fromacidifying aqueous layer and extracting with ethyl acetate andpurification to give a final 72% yield.

Step 2. 61-2 (130.00 mg, 347.30 μmol) and tert-butyl(R)-(2-hydroxypropyl)carbamate (182.56 mg, 1.04 mmol) were combined intoluene and was dried azeotropically under reduced pressure. Theresulting dried compounds were dissolved in dichloromethane (231.53 μL)and triphenylphosphine (277.83 mg, 1.06 mmol) was added into thesolution at room temperature. After ˜10 minutes, the mixture was cooledin an ice bath and DIAD (214.19 mg, 1.06 mmol, 207.95 μL) was added. Thereaction was stirred gradually to room temperature and stirred for 19hour, quenched by addition to water (4 solvent volume), and extractedwith DCM (3×3 mL). The combined extracts were dried with Na₂SO₄ andconcentrated under reduced pressure. Flash chromatography (ISCO system,silica (12 g), 0-100% ethyl acetate in hexane) to provide 61-3 (138.5mg, 57% yield).

Step 3. To a solution of 61-3 (138.50 mg, 201.09 μmol) in methanol (0.5mL), THF (2.00 mL) and water (1.80 mL) was added LiOH (2.0 M, 0.15 mL).The mixture was stirred at room temperature until the hydrolysis wascomplete. The reaction was neutralized to pH ˜5 with HCl, and extractedwith DCM. The combined extracts were dried with Na₂SO₄, filtered,concentrated, and dried in high vacuum to provide 61-4 (100 mg).

Step 4. To a solution of 61-4 (53.5 mg, 0.10 mmol) in DCM (4.5 mL) andDMF (0.5 mL) was added FDPP (50.3 mg, 0.13 mmol). Hünig's base (130.1mg, 1.01 mmol) and methylamine HCl salt (13.6 mg, 0.20 mmol). Themixture was stirred until LC-MS showed the completion, and then quenchedwith aqueous Na₂CO₃ solution. The mixture was extracted with DCM (3×50mL), and the combined extracts were dried with Na₂SO₄ and concentratedunder reduced pressure. Flash chromatography (ISCO system, silica (40g), 0-8.75% methanol in dichloromethane) provided 61-5 (24.4 mg, 44%yield)

61-5 was converted to 61 following the reaction step 4 in General methodH.

Compounds 27-31 were prepared according to General Method F using A-5and (S)-1-((tert-butoxycarbonyl)amino)butan-2-yl methanesulfonate for27, (S)-1-((tert-butoxycarbonyl)amino)propan-2-yl methanesulfonate for28, (R)-1-((tert-butoxycarbonyl)amino)propan-2-yl methanesulfonate for29, (R)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate for 30,and (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate for 31 instep 1.

Compound 32 was prepared according to General Method F using A-6 and(R)-1-((tert-butoxycarbonyl)amino)propan-2-yl methanesulfonate in step1.

Compounds 34 and 35 were prepared according to General Methods A and Fusing ethyl 3-ethoxy-2-methylacrylate in General Method A to get ethyl5-chloro-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate in replacementof ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (A-1-8), andusing tert-butyl (2-chloroethyl)carbamate for 34 and(R)-1-((tert-butoxycarbonyl)amino)propan-2-yl methanesulfonate for 35 inGeneral Method F.

Compounds 36 and 37 were prepared according to General Methods A and Fusing A-1-8 for 36 and ethyl5-chloro-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate for 37, and2-hydroxybenzaldehyde in place of 5-fluoro-2-hydroxybenzaldehyde inGeneral Method A, and using tert-butyl (2-chloroethyl)carbamate for both36 and 37 in General Method F.

Compound 39 was prepared according to General Methods A and F usingethyl 5-amino-3-ethyl-1H-pyrazole-4-carboxylate in place of ethyl5-amino-1H-pyrazole-4-carboxylate (A-1-6) in General Method A, and using(R)-1-((tert-butoxycarbonyl)amino)propan-2-yl methanesulfonate inGeneral Method F.

Compound 40 was prepared according to General Method I using 40-5 inplace of 33-3.

Compounds 42-54 were prepared according to General Method L using thefollowing starting material in place of (1S,2S)-2-aminocyclopentan-1-olin General Method L.

Starting material in place of Compound # 41-1 in General Method L 41(1S,2S)-2-aminocyclopentan-1-ol 42 (1R,2R)-2-aminocyclopentan-1-ol 43(1S,2R)-2-aminocyclopentan-1-ol 44 (1R,2S)-2-aminocyclohexan-1-ol 45(1S,2R)-2-aminocyclohexan-1-ol 46 (1R,2S)-2-aminocyclopentan-1-ol 47(1R,2R)-2-aminocyclohexan-1-ol 48 (3S,4S)-4-aminopyrrolidin-3-ol 49(3R,4S)-4-aminopyrrolidin-3-ol 50 (R)-pyrrolidin-3-ol 51(S)-pyrrolidin-3-ol 52 (R)-piperidin-3-ol 53 (S)-piperidin-3-ol 54piperidin-4-ol

Compounds 55-57 were prepared according to General Method E usingcompound 7 in place of compound 6, and dimethylamine for 55, methylaminefor 56, and pyrrolidine for 57.

Compounds 59 and 60 were prepared according to General Method M usingtert-butyl (R)-(2-hydroxypropyl)carbamate in place of tert-butyl(S)-(2-hydroxypropyl)carbamate in place of tert-butyl(S)-(2-hydroxybutyl)carbamate.

Compound 62 was prepared according to General Method N using dimethylamine in place of methylamine.

Compd MS # Structure m/z ¹H NMR (500 MHz, DMSO-d₆) δ ppm  1

370.2 9.35 (br t, J = 4.58 Hz, 1 H), 8.73 (d, J = 5.73 Hz, 1 H), 8.58(d, J = 7.45 Hz, 1 H), 8.04 (s, 1 H), 7.05-7.12 (m, 2 H), 6.91 (td, J =8.59, 3.44 Hz, 1 H), 6.38 (d, J = 7.45 Hz, 1 H), 5.48-5.61 (m, 1 H),4.46-4.58 (m, 1 H), 3.59-3.77 (m, 2 H), 1.92-2.05 (m, 2 H), 1.50-1.63(m, 1 H), 1.43 (d, J = 6.87 Hz, 3 H), 0.94 (t, J = 7.45 Hz, 3 H)  2

370.2 9.94 (d, J = 9.17 Hz, 1 H), 8.78 (d, J = 7.45 Hz, 1 H), 8.58 (d, J= 7.45 Hz, 1 H), 8.04 (s, 1 H), 7.16 (dd, J = 9.74, 3.44 Hz, 1 H),6.98-7.05 (m, 1 H), 6.91-6.97 (m, 1 H), 6.33 (d, J = 7.45 Hz, 1 H), 5.66(m, 1 H), 4.48 (d, J = 9.74 Hz, 1 H), 3.99-4.09 (m, 1 H), 3.84 (dd, J =9.74, 3.44 Hz, 1 H), 1.68- 1.82 (m, 2 H), 1.46 (d, J = 7.45 Hz, 3 H),0.99 (t, J = 7.45 Hz, 3 H)  3

370.2 9.69 (dd, J = 6.30, 3.44 Hz, 1 H), 8.80 (d, J = 6.87 Hz, 1 H),8.58 (d, J = 7.45 Hz, 1 H), 8.03 (s, 1 H), 7.09-7.14 (m, 1 H), 7.03 (dd,J = 9.17, 4.58 Hz, 1 H), 6.92-6.98 (m, 1 H), 6.37 (d, J = 7.45 Hz, 1 H),5.46-5.57 (m, 1 H), 4.41-4.49 (m, 1 H), 3.88 (ddd, J = 13.60, 6.73, 4.30Hz, 1 H), 3.22 (ddd, J = 13.75, 7.45, 3.44 Hz, 1 H), 1.85-1.97 (m, 1 H),1.74-1.82 (m, 1 H), 1.44 (d, J = 6.87 Hz, 3 H), 1.02 (t, J = 7.45 Hz, 3H)  4

370.2 9.28 (d, J = 2.29 Hz, 1 H), 8.71 (d, J = 6.87 Hz, 1 H), 8.56 (d, J= 8.02 Hz, 1 H), 8.01 (s, 1 H), 7.16 (dd, J = 9.17, 2.86 Hz, 1 H),7.07-7.11 (m, 1 H), 6.98-7.06 (m, 1 H), 6.34 (d, J = 7.45 Hz, 1 H),5.63-5.72 (m, 1 H), 4.40 (dd, J = 10.31, 4.01 Hz, 1 H), 4.05 (dd, J =10.31, 8.59 Hz, 1 H), 3.81- 3.92 (m, 1 H), 2.10-2.30 (m, 1 H), 1.87 (dt,J = 14.46, 7.37 Hz, 1 H), 1.42 (d, J = 6.87 Hz, 3 H), 0.97 (t, J = 7.45Hz, 3 H)  5

372.2 9.73 (dd, J = 7.73, 2.58 Hz, 1 H), 8.82 (d, J = 6.30 Hz, 1 H),8.51-8.63 (m, 1 H), 8.03 (s, 1 H), 7.15 (dd, J = 9.16, 4.58 Hz, 1 H),7.11 (dd, J = 9.45, 3.15 Hz, 1 H), 6.94- 7.00 (m, 1 H), 6.37 (d, J =8.02 Hz, 1 H), 5.47-5.55 (m, 1 H), 5.14 (t, J = 5.73 Hz, 1 H), 4.40-4.46(m, 1 H), 3.93 (ddd, J = 13.75, 7.73, 4.30 Hz, 1 H), 3.77 (dt, J =11.17, 5.30 Hz, 1 H), 3.69 (dt, J = 11.74, 6.16 Hz, 1 H), 3.26 (ddd, J =13.60, 7.88, 3.15 Hz, 1 H), 1.44 (d, J = 6.87 Hz, 3 H)  6

372.2 9.62 (d, J = 3.44 Hz, 1 H), 8.79 (d, J = 6.87 Hz, 1 H), 8.59 (d, J= 7.45 Hz, 1 H), 8.06 (s, 1 H), 7.14 (dd, J = 9.45, 3.15 Hz, 1 H), 7.10(dd, J = 9.17, 4.58 Hz, 1 H), 6.99- 7.04 (m, 1 H), 6.37 (d, J = 7.45 Hz,1 H), 5.60-5.67 (m, 1 H), 5.54 (dd, J = 7.73, 4.30 Hz, 1 H), 4.42 (dd, J= 10.88, 4.58 Hz, 1 H), 4.28 (dd, J = 10.88, 7.45 Hz, 1 H), 3.91-3.99(m, 1 H), 3.83 (ddd, J = 11.03, 6.16, 4.58 Hz, 1 H), 3.44-3.54 (m, 1 H),1.43 (d, J = 6.87 Hz, 3 H)  7

372.2 9.27 (dd, J = 6.87, 1.72 Hz, 1 H), 8.74 (d, J = 5.16 Hz, 1 H),8.59 (d, J = 7.45 Hz, 1 H), 8.02 (s, 1 H), 7.29 (dd, J = 9.16, 4.58 Hz,1 H), 7.05 (dd, J = 9.45, 3.15 Hz, 1 H), 6.85- 6.94 (m, 1 H), 6.40 (d, J= 7.45 Hz, 1 H), 5.36-5.48 (m, 1 H), 5.19 (t, J = 5.44 Hz, 1 H), 4.56(dq, J = 9.88, 5.11 Hz, 1 H), 3.90 (dt, J = 11.74, 5.01 Hz, 1 H),3.71-3.79 (m, 2 H), 3.59-3.70 (m, 1 H), 1.43 (d, J = 6.87 Hz, 3 H)  8

372.2 9.93 (d, J = 8.59 Hz, 1 H), 8.80 (d, J = 6.87 Hz, 1 H), 8.58 (d, J= 7.45 Hz, 1 H), 8.05 (s, 1 H), 7.16 (dt, J = 9.17, 1.72 Hz, 1 H), 7.02(dd, J = 6.01, 1.43 Hz, 2 H), 6.34 (d, J = 7.45 Hz, 1 H), 5.59-5.71 (m,1 H), 5.11 (dd, J = 6.59, 4.87 Hz, 1 H), 4.66 (d, J = 9.17 Hz, 1H),4.01-4.13 (m, 1 H), 3.86 (dd, J = 9.74, 3.44 Hz, 1 H), 3.55-3.64 (m, 1H), 3.50-3.55 (m, 1 H), 1.45 (d, J = 7.45 Hz, 3 H)  9

374.2 9.70 (dd, J = 7.16, 3.15 Hz, 1 H), 8.84 (d, J = 6.30 Hz, 1 H),8.59 (d, J = 8.02 Hz, 1 H), 8.04 (s, 1 H), 7.08-7.18 (m, 2 H), 6.92-7.02 (m, 1 H), 6.38 (d, J = 7.45 Hz, 1 H), 5.51 (quind, J = 6.80, 6.80,6.80, 6.80, 1.43 Hz, 1 H), 4.66-4.91 (m, 3 H), 3.92 (ddd, J = 14.03,7.16, 4.01 Hz, 1 H), 3.33-3.38 (m, 1 H), 1.45 (d, J = 7.45 Hz, 3 H) 10

374.2 9.22-9.32 (m, 1 H), 8.78 (d, J = 5.16 Hz, 1 H), 8.60 (d, J = 7.45Hz, 1 H), 8.04 (s, 1 H), 7.16-7.25 (m, 1 H), 7.07 (dd, J = 9.16, 3.44Hz, 1 H), 6.86-6.96 (m, 1 H), 6.42 (d, J = 7.45 Hz, 1 H), 5.33-5.45 (m,1 H), 4.71-5.07 (m, 3 H), 3.78-3.90 (m, 1 H), 3.68 (ddd, J = 14.03,10.60, 1.72 Hz, 1 H), 1.44 (d, J = 6.87 Hz, 3 H) 11

374.2 10.04 (d, J = 8.59 Hz, 1 H), 8.83 (d, J = 7.45 Hz, 1 H), 8.59 (d,J = 8.02 Hz, 1 H), 8.07 (s, 1 H), 7.17 (dd, J = 9.17, , 2.86 Hz, 1 H),6.96-7.06 (m, 2 H), 6.35 (d, J = 8.02 Hz, 1 H), 5.60-5.72 (m, 1 H),4.48-4.74 (m, 3 H), 4.37-4.47 (m, 1 H), 3.98 (dt, J = 10.31, 3.44 Hz, 1H), 1.46 (d, J = 6.87 Hz, 3 H) 12

399.2 9.64 (dd, J = 6.59, 3.72 Hz, 1 H), 8.83 (d, J = 6.30 Hz, 1 H),8.55-8.62 (m, 1 H), 8.02 (s, 1 H), 7.08-7.17 (m, 2H), 6.93-7.02 (m, 1H), 6.38 (d, J = 8.02 Hz, 1 H), 5.44- 5.55 (m, 1 H), 4.57-4.66 (m, 1 H),3.87 (ddd, J = 13.60, 6.73, 4.30 Hz, 1 H), 3.35 (dd, J = 7.16, 3.72 Hz,1 H), 2.59-2.71 (m, 2 H), 2.27 (s, 6 H), 1.43 (d, J = 6.87 Hz, 3 H) 13

399.2 10.31 (br dd, J = 4.87, 2.58 Hz, 1 H), 9.96 (s, 1 H), 8.95 (d, J =7.45 Hz, 1 H), 8.60 (d, J = 8.02 Hz, 1 H), 8.12 (s, 1 H), 7.16-7.25 (m,1 H), 7.03-7.11 (m, 1 H), 6.98 (dd, J = 9.17, 4.01 Hz, 1 H), 6.38 (d, J= 7.45 Hz, 1 H), 5.61-5.72 (m, 1 H), 4.49 (td, J = 10.17, 2.58 Hz, 1 H),4.42 (dd, J = 9.45, 3.72 Hz, 1 H), 3.88 (t, J = 10.02 Hz, 1 H), 3.59 (brs, 1 H), 3.59-3.59 (m, 1 H), 3.25 (br dd, J = 12.89, 8.88 Hz, 1 H), 2.94(d, J = 4.58 Hz, 3 H), 2.93 (d, J = 5.16 Hz, 3 H), 1.42 (d, J = 6.87 Hz,3 H) 14

399.2 9.18 (br d, J = 7.14 Hz, 1 H), 8.77 (d, J = 4.94 Hz, 1 H), 8.59(d, J = 7.68 Hz, 1 H), 8.14 (q, J = 4.40 Hz, 1 H), 8.02 (s, 1 H), 7.08(dd, J = 9.33, 3.29 Hz, 1 H), 6.92 (td, J = 8.51, 3.29 Hz, 1 H), 6.74(dd, J = 8.78, 4.39 Hz, 1 H), 6.43 (d, J = 7.68 Hz, 1 H), 5.42 (dt, J =6.60 Hz, 1 H), 5.12 (dd, J = 10.43, 4.94 Hz, 1 H), 4.01 (ddd, J = 14.00,7.96, 5.49 Hz, 1 H), 3.62-3.69 (m, 1 H), 2.62 (d, J = 4.39 Hz, 3 H),1.52 (d, J = 7.14 Hz, 3 H) 15

399.2 9.84 (br d, J = 8.23 Hz, 1 H), 8.84 (d, J = 7.14 Hz, 1 H), 8.58(d, J = 7.68 Hz, 1 H), 8.21 (dt, J = 4.40 Hz, 1 H), 8.05 (s, 1 H) 7.18(dd, J = 9.33, 3.29 Hz, 1 H), 6.96- 7.03 (m, 1 H), 6.72 (dd, J = 9.33,4.39 Hz, 1 H), 6.37 (d, J = 7.68 Hz, 1 H), 5.59-5.69 (m, 1 H), 4.53 (dd,J = 9.88, 3.84 Hz, 1 H), 4.18 (ddd, J = 13.31, 9.19, 3.84 Hz, 1 H),3.25-3.29 (m, 1 H), 2.70 (d, J = 4.39 Hz, 3 H), 1.53 (d, J = 7.14 Hz, 3H) 16

392.2 9.54 (s, 1 H), 8.82 (d, J = 6.87 Hz, 1 H), 8.60 (d, J = 7.45 Hz, 1H), 8.08 (s, 1 H), 7.17 (dd, J = 9.45, 3.15 Hz, 1 H), 7.08- 7.12 (m, 1H), 7.02-7.07 (m, 1 H), 6.65- 6.96 (m, 1 H), 6.65-6.96 (m, 1 H), 6.39(d, J = 7.45 Hz, 1 H), 5.61 (quind, J = 7.02, 7.02, 7.02, 7.02, 1.72 Hz,1 H), 4.58-4.71 (m, 1 H), 4.37-4.51 (m, 2 H), 1.42 (d, J = 6.87 Hz, 3 H)17

392.2 10.23 (d, J = 8.59 Hz, 1 H), 8.86 (d, J = 7.45 Hz, 1 H), 8.60 (d,J = 7.45 Hz, 1 H), 8.10 (s, 1 H), 7.18 (dd, J = 9.45, 3.15 Hz, 1 H),7.00-7.09 (m, 1 H), 6.91-7.00 (m, 1 H), 6.36 (d, J = 7.45 Hz, 1 H),6.21-6.48 (m, 1 H), 5.61-5.73 (m, 1 H), 4.67 (d, J = 10.31 Hz, 1 H),4.40-4.56 (m, 1 H), 3.96-4.09 (m, 1 H), 1.45 (d, J = 6.87 Hz, 3 H) 18

392.2 9.67 (dd, J = 6.30, 3.44 Hz, 1 H), 8.87 (d, J = 6.30 Hz, 1 H),8.60 (d, J = 7.45 Hz, 1 H), 8.05 (s, 1 H), 7.17 (dd, J = 9.17, 4.58 Hz,1 H), 7.14 (dd, J = 9.45, 3.15 Hz, 1 H), 7.01 (ddd, J = 9.02, 7.88, 3.15Hz, 1 H), 6.32- 6.61 (m, 2 H), 5.40-5.54 (m, 1 H), 4.94- 5.09 (m, 1 H),3.90-4.00 (m, 1 H), 3.46 (ddd, J = 14.03, 6.87, 3.72 Hz, 1 H), 1.45 (d,J = 7.45 Hz, 3 H) 19

356.2 9.74 (dd, J = 7.45, 2.29 Hz, 1 H), 8.75 (d, J = 6.87 Hz, 1 H),8.53-8.63 (m, 1 H), 8.04 (s, 1 H), 7.05-7.17 (m, 1H), 6.96-7.04 (m, 2H), 6.37 (d, J = 7.45 Hz, 1 H), 5.39 (qd, J = 7.64, 1.72 Hz, 1 H), 4.51(dt, J = 10.02, 3.58 Hz, 1 H), 3.98 (td, J = 9.74, 3.44 Hz, 1 H), 3.86(ddt, J = 13.82, 7.52, 3.94, 3.94 Hz, 1 H), 3.35-3.46 (m, 1 H),1.83-2.03 (m, 1 H), 1.63-1.74 (m, 1 H), 0.87 (t, J = 7.45 Hz, 3 H) 20

384.2 9.64 (dd, J = 6.59, 3.72 Hz, 1 H), 8.78 (d, J = 6.30 Hz, 1 H),8.53-8.61 (m, 1 H), 8.02 (s, 1 H), 6.99-7.09 (m, 2 H), 6.90-6.98 (m, 1H), 6.38 (d, J = 7.45 Hz, 1 H), 5.23- 5.33 (m, 1 H), 4.43-4.53 (m, 1 H),3.84 (ddd, J = 13.60, 6.44, 4.58 Hz, 1 H), 3.23 (ddd, J = 13.60, 6.73,3.72 Hz, 1 H), 1.91- 1.98 (m, 1 H), 1.85-1.91 (m, 1 H), 1.75- 1.83 (m, 1H), 1.65-1.72 (m, 1 H), 1.02 (t, J = 7.45 Hz, 3 H), 0.86 (t, J = 7.45Hz, 3 H) 21

384.2 9.28 (d, J = 2.29 Hz, 1 H), 8.68 (d, J = 7.45 Hz, 1 H), 8.51-8.60(m, 1 H), 8.01 (s, 1 H), 7.06-7.16 (m, 2 H), 6.98-7.06 (m, 1 H), 6.36(d, J = 7.45 Hz, 1 H), 5.43 (qd, J = 7.64, 1.72 Hz, 1 H), 4.41 (dd, J =10.31, 4.01 Hz, 1 H), 4.02 (dd, J = 10.31, 8.59 Hz, 1 H), 3.79-3.92 (m,1 H), 2.13-2.30 (m, 1 H), 1.80-1.96 (m, 2 H), 1.65 (dt, J = 13.75, 7.45Hz, 1 H), 0.97 (t, J = 7.45 Hz, 3 H), 0.82 (t, J = 7.45 Hz, 3 H) 22

372.2 9.75 (dd, J = 7.73, 2.00 Hz, 1 H), 8.72 (d, J = 7.45 Hz, 1 H),8.57 (d, J = 7.45 Hz, 1 H), 8.05 (s, 1 H), 7.11 (dt, J = 9.17, 1.72 Hz,1 H), 6.97-7.04 (m, 2 H), 6.37 (d, J = 8.02 Hz, 1 H), 5.61-5.71 (m, 1H), 4.58 (t, J = 4.87 Hz, 1 H) 4.50 (dt, J = 10.17, 3.79 Hz, 1 H), 3.98(td, J = 9.74, 4.01 Hz, 1 H), 3.82-3.91 (m, 1 H), 3.35-3.56 (m, 3 H),2.05 (ddt, J = 13.89, 8.74, 5.58, 5.58 Hz, 1 H), 1.78 (dq, J = 13.68,6.71 Hz, 1 H) 23

374.2 9.71 (dd, J = 7.73, 2.00 Hz, 1 H), 8.82 (d, J = 7.45 Hz, 1 H),8.60 (d, J = 7.45 Hz, 1 H), 8.06 (s, 1 H), 7.12-7.22 (m, 1 H), 6.97-7.06 (m, 2 H), 6.38 (d, J = 8.02 Hz, 1 H), 5.64-5.77 (m, 1 H), 4.34-4.62(m, 3 H), 3.97 (td, J = 9.74, 4.01 Hz, 1 H), 3.84-3.91 (m, 1 H),3.35-3.42 (m, 1 H), 2.22-2.35 (m, 1 H), 1.98-2.12 (m, 1 H) 24

386.2 9.70 (dd, J = 7.45, 2.86 Hz, 1 H), 8.75 (d, J = 7.45 Hz, 1 H),8.53-8.61 (m, 1 H), 8.02 (s, 1 H), 7.17-7.25 (m, 1H), 6.97-7.02 (m, 2H), 6.67 (d, J = 8.02 Hz, 1 H), 5.42 (dd, J = 7.73, 1.43 Hz, 1 H), 5.01(s, 1 H), 4.52 (dt, J = 10.31, 4.01 Hz, 1 H), 4.02 (ddd, J = 10.31,9.17, 4.01 Hz, 1 H), 3.79- 3.88 (m, 1 H), 3.35-3.44 (m, 1 H), 1.32 (s, 3H), 0.97 (s, 3 H) 25

386.2 9.28 (dd, J = 6.01, 2.58 Hz, 1 H), 8.75 (d, J = 5.73 Hz, 1 H),8.59 (d, J = 7.45 Hz, 1 H), 8.03 (s, 1 H), 7.24 (dd, J = 8.88, 4.87 Hz,1 H), 7.06 (dd, J = 9.17, 3.44 Hz, 1 H), 6.87- 6.95 (m, 1 H), 6.40 (d, J= 8.02 Hz, 1 H), 5.37-5.47 (m, 1 H), 4.72 (dq, J = 9.31, 4.92 Hz, 1 H),3.84 (dd, J = 10.88, 5.16 Hz, 1 H), 3.62-3.77 (m, 3 H) 3.31 (s, 3 H),1.43 (d, J = 6.87 Hz, 3 H) 26

359.2 9.41 (dd, J = 6.01, 3.72 Hz, 1 H), 8.69 (d, J = 6.87 Hz, 1 H),8.58 (d, J = 7.45 Hz, 1 H), 8.06 (s, 1 H), 7.14 (dd, J = 9.45, 3.15 Hz,1 H), 7.07 (dd, J = 9.17, 4.58 Hz, 1 H), 6.90- 7.01 (m, 1 H), 6.35 (d, J= 7.45 Hz, 1 H), 5.68 (br d, J = 6.30 Hz, 1 H), 4.78-4.88 (m, 1 H), 3.79(dt, J = 13.46, 5.87 Hz, 1 H), 3.55 (dt, J = 13.75, 3.44 Hz, 1 H), 1.19(br d, J = 5.73 Hz, 3 H) 27

356.2 9.76 (dd, J = 6.87, 2.86 Hz, 1 H), 8.94 (t, J = 6.01 Hz, 1 H),8.58 (d, J = 7.45 Hz, 1 H), 8.04 (s, 1 H), 7.10 (dd, J = 9.16, 2.86 Hz,1 H), 7.00-7.05 (m, 1 H), 6.95-7.00 (m, 1 H), 6.41 (d, J = 8.02 Hz, 1H), 5.06 (ddd, J = 14.61, 6.01, 1.15 Hz, 1 H), 4.40-4.46 (m, 1 H), 3.96(dd, J = 14.32, 5.73 Hz, 1 H), 3.91 (ddd, J = 13.60, 7.30, 4.30 Hz, 1H), 3.21 (ddd, J = 13.60, 7.59, 2.86 Hz, 1 H), 1.86-1.96 (m, 1 H),1.73-1.82 (m, 1 H), 1.02 (t, J = 7.45 Hz, 3 H) 28

342.2 9.83-9.92 (m, 1 H), 8.94 (t, J = 6.01 Hz, 1 H), 8.58 (d, J = 7.45Hz, 1 H), 8.04 (s, 1 H), 7.12 (dd, J = 9.17, 2.86 Hz, 1 H), 6.94- 7.06(m, 2 H), 6.40 (d, J = 7.45 Hz, 1 H), 5.08 (ddd, J = 14.61, 6.59, 1.72Hz, 1 H), 4.42-4.52 (m, 1 H), 3.85-4.02 (m, 2 H), 3.13 (ddd, J = 13.60,8.74, 2.29 Hz, 1 H), 1.45 (d, J = 5.73 Hz, 3 H) 29

342.2 9.83-9.90 (m, 1 H), 8.94 (t, J = 6.01 Hz, 1 H), 8.55-8.61 (m, 1H), 8.04 (s, 1 H), 7.12 (dd, J = 9.45, 3.15 Hz, 1 H), 6.94- 7.06 (m, 2H), 6.40 (d, J = 8.02 Hz, 1 H), 5.08 (ddd, J = 14.46, 6.73, 1.72 Hz, 1H), 4.43-4.51 (m, 1 H), 3.87-4.00 (m, 2 H), 3.13 (ddd, J = 13.46, 8.88,2.29 Hz, 1 H), 1.45 (d, J = 5.73 Hz, 3 H) 30

342.2 10.02 (d, J = 8.59 Hz, 1 H), 8.90 (t, J = 6.30 Hz, 1 H), 8.58 (d,J = 7.45 Hz, 1 H), 8.04 (s, 1 H), 7.15 (dd, J = 9.17, 3.44 Hz, 1 H),7.00-7.08 (m, 1 H), 6.93-6.99 (m, 1 H), 6.38 (d, J = 8.02 Hz, 1 H), 5.20(ddd, J = 14.46, 7.30, 1.72 Hz, 1 H), 4.34 (dd, J = 9.16, 1.15 Hz, 1 H),4.23-4.31 (m, 1 H), 3.98 (dd, J = 14.32, 5.73 Hz, 1 H), 3.88 (dd, J =9.45, 3.72 Hz, 1 H), 1.37 (d, J = 6.87 Hz, 3 H) 31

342.2 9.96-10.07 (m, 1 H), 8.84-8.93 (m, 1 H), 8.58 (dd, J = 7.73, 4.87Hz, 1 H), 8.04 (d, J = 4.58 Hz, 1 H), 7.11-7.21 (m, 1 H), 7.00-7.09 (m,1 H), 6.91-6.98 (m, 1 H), 6.38 (dd, J = 7.45, 4.58 Hz, 1 H), 5.15- 5.25(m, 1 H), 4.34 (dd, J = 9.45, 3.15 Hz, 1 H), 4.21-4.32 (m, 1 H),3.93-4.03 (m, 1 H), 3.84-3.91 (m, 1 H), 1.37 (dd, J = 6.30, 4.58 Hz, 3H) 32

339.2 9.85 (br d, J = 7.45 Hz, 1 H), 8.83 (d, J = 6.87 Hz, 1 H), 8.53(d, J = 7.45 Hz, 1 H), 8.12 (dd, J = 4.58, 1.15 Hz, 1 H), 8.02 (s, 1 H),7.45 (d, J = 8.59 Hz, 1 H), 7.15-7.25 (m, 1 H), 6.40 (d, J = 8.02 Hz, 1H), 5.64 (quin, J = 6.87 Hz, 1 H), 4.49 (ddd, J = 9.31, 5.87, 3.72 Hz, 1H), 3.91-4.01 (m, 1 H), 3.14 (ddd, J = 13.32, 9.02, 1.72 Hz, 1 H),1.44-1.52 (m, 6H) 33

324.2 12.02 (br d, J = 2.29 Hz, 1 H), 10.32 (dd, J = 7.16, 2.58 Hz, 1H), 7.79-7.86 (m, 2 H), 7.70 (s, 1 H), 7.42 (dd, J = 7.45, 1.72 Hz, 1H), 7.09-7.16 (m, 1 H), 6.95 (d, J = 7.45 Hz, 1 H), 6.88-6.93 (m, 1 H),5.55 (quin, J = 7.02 Hz, 1 H), 4.50 (dt, J = 10.17, 4.08 Hz, 1 H),4.05-4.13 (m, 1 H), 3.89 (ddt, J = 13.75, 7.59, 3.94, 3.94 Hz, 1 H),3.41-3.49 (m, 1 H), 1.43 (d, J = 7.45 Hz, 3 H) 34

356.2 9.58-9.69 (m, 1 H), 8.58 (d, J = 1.15 Hz, 1 H), 7.97-8.05 (m, 2H), 7.42 (dt, J = 9.74, 1.72 Hz, 1 H), 6.99 (dd, J = 6.30, 1.72 Hz, 2H), 5.72-5.82 (m, 1 H), 4.52 (dt, J = 9.88, 3.65 Hz, 1 H), 3.97 (td, J =9.88, 3.72 Hz, 1 H), 3.83-3.92 (m, 1 H), 3.37-3.44 (m, 1 H), 2.18 (d, J= 1.15 Hz, 3 H), 1.51 (d, J = 6.87 Hz, 3 H) 35

370.2 9.70-9.77 (m, 1 H), 8.57 (d, J = 1.15 Hz, 1 H), 8.03 (d, J = 7.45Hz, 1 H), 7.99 (s, 1 H), 7.37 (dd, J = 9.74, 2.86 Hz, 1 H), 6.99- 7.04(m, 1 H), 6.92-6.98 (m, 1 H), 5.63- 5.72 (m, 1 H), 4.41-4.50 (m, 1 H),3.87- 3.96 (m, 1 H), 3.13 (ddd, J = 13.46, 8.88, 1.72 Hz, 1 H), 2.20 (d,J = 1.15 Hz, 3 H), 1.50 (d, J = 7.45 Hz, 3 H), 1.46 (d, J = 5.73 Hz, 3H) 36

324.2 9.79 (dd, J = 7.45, 2.29 Hz, 1 H), 8.83 (d, J = 6.87 Hz, 1 H),8.53-8.59 (m, 1 H), 8.03 (s, 1 H), 7.36 (dd, J = 8.02, 1.72 Hz, 1 H),7.14-7.20 (m, 1 H), 6.91-7.02 (m, 2 H), 6.34 (d, J = 8.02 Hz, 1 H), 5.66(quin, J = 7.02 Hz, 1 H), 4.49 (dt, J = 10.17, 3.79 Hz, 1 H), 4.03 (td,J = 9.74, 4.01 Hz, 1 H), 3.87 (ddt, J = 13.75, 7.73, 3.58, 3.58 Hz, 1H), 3.37-3.45 (m, 1 H), 1.45 (d, J = 6.87 Hz, 3 H) 37

338.2 9.70 (dd, J = 7.73, 2.00 Hz, 1 H), 8.55 (d, J = 1.72 Hz, 1 H),8.06 (d, J = 6.87 Hz, 1 H), 7.99 (s, 1 H), 7.56 (dd, J = 8.02, 1.72 Hz,1 H), 7.12-7.20 (m, 1 H), 6.90-7.00 (m, 2 H), 5.81 (quin, J = 7.16 Hz, 1H), 4.50 (dt, J = 10.02, 3.58 Hz, 1 H), 4.01 (td, J = 9.74, 4.01 Hz, 1H), 3.89 (ddt, J = 13.68, 7.52, 3.72, 3.72 Hz, 1 H), 3.37-3.46 (m, 1 H),2.18 (d, J = 1.15 Hz, 3 H), 1.51 (d, J = 7.45 Hz, 3 H) 38

381.2 9.69-9.77 (m, 1 H), 9.10 (d, J = 6.87 Hz, 1 H), 8.66 (d, J = 7.45Hz, 1 H), 8.09 (s, 1 H), 7.20 (dd, J = 8.88, 2.58 Hz, 1 H), 7.03- 7.10(m, 2 H), 6.44 (d, J = 7.45 Hz, 1 H), 5.75-5.83 (m, 1 H), 4.45-4.54 (m,1 H), 3.93 (ddd, J = 13.03, 8.74, 4.01 Hz, 1 H), 3.13-3.17 (m, 1 H),1.46 (d, J = 6.30 Hz, 3 H) 39

384.2 9.85 (dd, J = 8.02, 2.29 Hz, 1 H), 8.72 (d, J = 6.30 Hz, 1 H),8.48 (d, J = 7.45 Hz, 1 H), 7.12 (dd, J = 9.45, 3.15 Hz, 1 H), 6.99-7.05 (m, 1 H), 6.91-6.99 (m, 1 H), 6.28 (d, J = 7.45 Hz, 1 H), 5.47-5.57(m, 1 H), 4.43-4.52 (m, 1 H), 3.90 (ddd, J = 13.46, 8.31, 3.44 Hz, 1 H),3.11 (ddd, J = 13.32, 8.45, 2.29 Hz, 1 H), 2.81-2.91 (m, 2 H), 1.45 (d,J = 6.30 Hz, 3 H), 1.43 (d, J = 6.87 Hz, 3 H), 1.17 (t, J = 7.45 Hz, 3H) 40

356.2 12.05 (d, J = 2.29 Hz, 1 H), 10.36 (dd, J = 8.02, 2.29 Hz, 1 H),7.79-7.87 (m, 2 H), 7.71 (s, 1 H), 7.21 (dd, J = 9.74, 2.86 Hz, 1 H),6.95-7.01 (m, 1 H), 6.86-6.94 (m, 1 H), 5.40-5.49 (m, 1 H), 4.49 (ddd, J= 8.31, 6.01, 4.01 Hz, 1 H), 3.94 (ddd, J = 13.60, 8.16, 4.01 Hz, 1 H),3.18 (ddd, J = 13.60, 8.45, 2.58 Hz, 1 H), 1.38-1.48 (m, 6 H) 41

382.2 9.76 (s, 1 H), 9.49 (d, J = 6.30 Hz, 1 H), 8.90 (d, J = 6.87 Hz, 1H), 8.55-8.62 (m, 2 H), 8.52 (d, J = 7.45 Hz, 1 H), 8.03 (s, 1 H), 8.00(s, 1 H), 7.20 (dd, J = 9.45, 3.15 Hz, 1 H), 6.91-7.09 (m, 5 H),6.28-6.36 (m, 2 H), 5.87-5.98 (m, 1 H), 4.96 (td, J = 8.02, 4.58 Hz, 1H), 4.86 (td, J = 5.87, 2.58 Hz, 1 H), 4.71 (quin, J = 7.16 Hz, 1 H),4.27-4.35 (m, 1 H), 4.14 (br s, 1 H), 2.96-3.05 (m, 1 H), 2.27-2.40 (m,1 H), 2.08-2.19 (m, 1 H), 1.98-2.07 (m, 1 H), 1.87-1.97 (m, 3 H),1.75-1.87 (m, 3 H), 1.58-1.68 (m, 4 H), 1.41 (d, J = 6.87 Hz, 3 H),1.25-1.33 (m, 1 H) 42

382.2 9.60 (d, J = 6.87 Hz, 1 H), 8.76 (d, J = 6.30 Hz, 1 H), 8.52-8.62(m, 1 H), 8.01 (s, 1 H), 7.10 (dd, J = 9.45, 3.15 Hz, 1 H), 6.99- 7.05(m, 1 H), 6.93-6.99 (m, 1 H), 6.35 (d, J = 7.45 Hz, 1 H), 5.50-5.60 (m,1 H), 4.85 (td, J = 5.87, 2.58 Hz, 1 H), 4.25 (quin, J = 6.59 Hz, 1 H),2.15-2.26 (m, 1 H), 1.98-2.07 (m, 1 H), 1.81-1.91 (m, 3 H), 1.59-1.69(m, 1 H), 1.45 (d, J = 6.87 Hz, 3 H) 43

382.2 8.99 (s, 1 H), 8.78 (d, J = 4.58 Hz, 1 H), 8.55-8.63 (m, 1 H),7.97 (s, 1 H), 7.14 (dd, J = 8.88, 4.87 Hz, 1 H), 6.95 (dd, J = 9.45,3.15 Hz, 1 H), 6.86 (td, J = 8.45, 3.15 Hz, 1 H), 6.43 (d, J = 7.45 Hz,1 H), 5.24-5.35 (m, 1 H), 4.54 (td, J = 10.88, 8.59 Hz, 1 H), 3.99 (td,J = 10.60, 7.45 Hz, 1 H), 2.52-2.61 (m, 1 H), 2.14-2.24 (m, 1 H),2.03-2.14 (m, 1 H), 1.80-1.93 (m, 1 H), 1.69-1.79 (m, 1 H), 1.47-1.57(m, 1H), 1.41 (d, J = 6.87 Hz, 3 H) 44

396.2 9.29 (s, 1 H), 8.77 (d, J = 7.45 Hz, 1 H), 8.55 (d, J = 8.02 Hz, 1H), 7.98 (s, 1 H), 7.16 (dd, J = 9.45, 3.15 Hz, 1 H), 6.97- 7.05 (m, 2H), 6.32 (d, J = 8.02 Hz, 1 H), 5.58 (td, J = 7.16, 1.72 Hz, 1 H),4.01-4.07 (m, 1 H), 3.54-3.60 (m, 1 H), 3.25-3.31 (m, 1 H), 2.21-2.27(m, 1 H), 1.69-1.78 (m, 2 H), 1.49-1.61 (m, 3 H), 1.42 (d, J = 7.45 Hz,3 H), 1.35 (td, J = 12.89, 2.29 Hz, 1 H) 45

396.2 8.73 (s, 1 H), 8.69 (d, J = 4.58 Hz, 1 H), 8.54 (d, J = 7.45 Hz, 1H), 7.96 (s, 1 H), 7.22 (dd, J = 9.17, 4.58 Hz, 1 H), 6.95 (dd, J =9.45, 3.15 Hz, 1 H), 6.81 (td, J = 8.59, 2.86 Hz, 1 H), 6.37 (d, J =8.02 Hz, 1 H), 5.32 (s, 1 H), 4.25-4.32 (m, 1 H), 4.04 (td, J = 10.60,4.01 Hz, 1 H), 3.17-3.22 (m, 1 H), 2.32-2.40 (m, 1 H), 2.08-2.13 (m, 1H), 1.82 (br d, J = 12.60 Hz, 1 H), 1.64 (br d, J = 12.03 Hz, 1 H),1.39-1.52 (m, 5 H), 1.19-1.27 (m, 1 H) 46

382.2 9.62 (s, 1 H), 8.82 (d, J = 7.45 Hz, 1 H), 8.58 (d, J = 7.45 Hz, 1H), 8.00 (s, 1 H), 7.13-7.19 (m, 1 H), 7.00-7.05 (m, 2 H), 6.35 (d, J =7.45 Hz, 1 H), 5.60-5.68 (m, 1 H), 4.01-4.09 (m, 1 H), 3.62-3.71 (m, 1H), 2.43-2.49 (m, 1 H), 2.27-2.37 (m, 1 H), 1.79-1.90 (m, 2 H),1.65-1.79 (m, 2 H), 1.42 (d, J = 6.87 Hz, 3 H) 47

396.2 1.41-1.50 (m, 5 H), 1.50-1.57 (m, 1 H), 1.62-1.67 (m, 1 H),1.71-1.83 (m, 3 H), 2.19-2.26 (m, 1 H), 3.88-3.97 (m, 1 H), 4.42 (br d,J = 2.86 Hz, 1 H), 5.58 (td, J = 7.16, 1.72 Hz, 1 H), 6.35 (d, J = 8.02Hz, 1 H), 6.93-6.98 (m, 2 H), 7.14 (dd, J = 9.74, 2.29 Hz, 1 H), 8.03(s, 1 H), 8.56- 8.59 (m, 1 H), 8.85 (d, J = 6.87 Hz, 1 H), 10.05 (d, J =9.74 Hz, 1 H) 48

383.2 1.40 (d, J = 7.45 Hz, 3 H), 3.14 (br dd, J = 12.32, 5.44 Hz, 1 H),3.56 (dd, J = 12.03, 6.87 Hz, 1 H), 3.60-3.69 (m, 1 H), 3.90 (br d, J =4.01 Hz, 1 H), 4.36-4.46 (m, 1 H), 5.24 (br s, 1 H), 5.86 (br t, J =6.87 Hz, 1 H), 6.27 (d, J = 7.45 Hz, 1 H), 7.02 (ddd, J = 9.16, 8.02,3.44 Hz, 1 H), 7.21-7.31 (m, 3 H), 7.60-7.67 (m, 1 H), 7.97 (s, 1 H),8.50 (d, J = 7.45 Hz, 1 H), 8.54 (d, J = 8.59 Hz, 1 H) 49

383.2 1.34 (br d, J = 7.45 Hz, 3 H), 1.41 (br d, J = 5.73 Hz, 1 H),1.86-2.30 (m, 2 H), 2.63 (br d, J = 9.74 Hz, 1 H), 3.43-3.53 (m, 3 H),3.62-3.70 (m, 1 H), 3.77-3.83 (m, 1 H), 3.83-3.92 (m, 1 H), 4.74 (br s,1 H), 4.97-5.07 (m, 1 H), 5.33-5.42 (m, 1 H), 6.05-6.15 (m, 1 H), 6.20(d, J = 7.45 Hz, 1 H), 6.38-6.44 (m, 1 H), 6.86-6.94 (m, 1 H), 6.99-7.07(m, 1 H), 7.10 (br d, J = 9.17 Hz, 1 H), 7.14 (dd, J = 9.17, 4.58 Hz, 1H), 7.20 (dd, J = 9.45, 3.15 Hz, 1 H), 7.90 (s, 1 H), 7.97 (br s, 1 H),8.20 (br d, J = 8.02 Hz, 1 H), 8.47 (d, J = 7.45 Hz, 1 H), 8.51-8.58 (m,1 H) 50

368.2 1.34 (br d, J = 7.45 Hz, 3 H), 1.82-1.94 (m, 1 H), 2.15 (br dd, J= 12.89, 4.87 Hz, 1 H), 2.95 (br t, J = 9.17 Hz, 1 H), 3.34-3.39 (m, 1H), 3.60 (br d, J = 11.46 Hz, 1 H), 3.90 (br d, J = 12.60 Hz, 1 H), 5.18(br s, 1 H), 6.07-6.17 (m, 1 H), 6.20 (d, J = 7.45 Hz, 1 H), 6.96-7.08(m, 2 H), 7.16-7.25 (m, 1 H), 7.91 (s, 1 H), 8.22 (br d, J = 8.02 Hz, 1H), 8.47 (br d, J = 7.45 Hz, 1 H) 51

368.2 1.38 (d, J = 6.87 Hz, 3 H), 2.02-2.12 (m, 1 H), 2.52-2.59 (m, 1H), 3.05 (dd, J = 12.03, 6.30 Hz, 1 H), 3.07-3.15 (m, 1 H), 3.95 (t, J =10.31 Hz, 1 H), 4.39 (d, J = 12.03 Hz, 1 H), 5.49 (dt, J = 8.02, 5.44Hz, 1 H), 5.71-5.79 (m, 2 H), 6.26 (d, J = 8.02 Hz, 1 H), 6.94-7.03 (m,1 H), 7.22 (dd, J = 9.74, 3.44 Hz, 1 H), 7.27 (dd, J = 9.17, 4.58 Hz, 1H), 7.97 (s, 1 H), 8.48 (d, J = 7.45 Hz, 1 H), 8.51 (d, J = 8.59 Hz, 1H) 52

382.2 1.43 (d, J = 6.87 Hz, 3 H), 1.67-1.83 (m, 2 H), 2.32 (br d, J =10.88 Hz, 1 H), 2.46- 2.49 (m, 1 H), 2.78-2.87 (m, 1 H), 4.09- 4.18 (m,1 H), 4.49-4.58 (m, 1 H), 4.94- 5.04 (m, 1 H), 5.29-5.38 (m, 1 H), 6.40(d, J = 8.02 Hz, 1 H), 6.81-6.90 (m, 1 H), 6.94 (dd, J = 9.17, 5.16 Hz,1 H), 7.06 (dd, J = 9.74, 2.86 Hz, 1 H), 8.03 (s, 1 H), 8.46 (d, J =6.87 Hz, 1 H), 8.51 (d, J = 7.45 Hz, 1 H) 53

382.2 1.42 (d, J = 7.45 Hz, 3 H), 1.55-1.66 (m, 1 H), 1.82 (dtt, J =13.25, 8.77, 8.77, 4.08, 4.08 Hz, 1 H), 1.92-2.03 (m, 1 H), 2.03- 2.13(m, 1 H), 3.26-3.31 (m, 1 H), 3.65 (ddd, J = 12.89, 6.59, 4.01 Hz, 1 H),3.74 (dd, J = 13.46, 4.87 Hz, 1 H), 4.20 (dd, J = 13.46, 3.15 Hz, 1 H),4.23-4.31 (m, 1 H), 5.94-6.04 (m, 1 H), 6.23 (d, J = 7.45 Hz, 1 H),6.94-7.02 (m, 1 H), 7.07 (dd, J = 9.17, 4.58 Hz, 1 H), 7.19 (dd, J =9.74, 3.44 Hz, 1 H), 8.04 (s, 1 H), 8.29 (d, J = 8.59 Hz, 1 H), 8.46 (d,J = 7.45 Hz, 1 H) 54

382.2 1.35 (d, J = 6.87 Hz, 3 H), 1.78-1.89 (m, 1 H), 2.01 (td, J =13.60, 7.16 Hz, 1 H), 2.15 (br d, J = 15.47 Hz, 1 H), 2.33-2.45 (m, 1H), 2.84 (dd, J = 10.60, 4.87 Hz, 1 H), 3.02 (td, J = 13.17, 5.16 Hz, 1H), 4.13 (ddd, J = 12.60, 11.17, 4.87 Hz, 1 H), 4.21 (dd, J = 13.17,6.87 Hz, 1 H), 5.05 (br d, J = 9.17 Hz, 1 H), 6.12-6.19 (m, 1 H), 6.20(d, J = 8.02 Hz, 1 H), 6.95-7.03 (m, 2 H), 7.24 (dd, J = 9.16, 2.29 Hz,1 H), 7.89 (s, 1 H), 8.39 (d, J = 9.17 Hz, 1 H), 8.47 (d, J = 7.45 Hz, 1H) 55

399.2 1.43 (d, J = 6.87 Hz, 3 H), 2.23 (s, 6 H), 2.65-2.84 (m, 2 H),3.66-3.77 (m, 2 H), 4.64-4.71 (m, 1 H), 5.42-5.51 (m, 1 H), 6.39 (d, J =7.45 Hz, 1 H), 6.91 (td, J = 8.45, 3.15 Hz, 1 H), 7.05-7.12 (m, 2 H),8.04 (s, 1 H), 8.59 (d, J = 7.45 Hz, 1 H), 8.74 (d, J = 5.73 Hz, 1 H),9.32 (br t, J = 4.01 Hz, 1 H) 56

385.2 1.43-1.48 (m, 3 H), 2.87-2.98 (m, 4 H), 3.56-3.66 (m, 1 H),3.88-4.12 (m, 2 H), 5.03 (br s, 1 H), 5.24-5.35 (m, 1 H), 6.41- 6.50 (m,1 H), 6.94 (td, J = 8.31, 3.44 Hz, 1 H), 7.04-7.13 (m, 1 H), 7.17-7.25(m, 1 H), 8.04 (s, 1 H), 8.59-8.65 (m, 1 H), 8.86 (d, J = 5.16 Hz, 1 H),9.23 (d, J = 8.59 Hz, 1 H), 9.75 (br s, 1 H) 57

425.2 1.23 (s, 4 H), 1.43 (d, J = 6.87 Hz, 3 H), 1.69 (br s, 4 H),2.79-3.07 (m, 2 H), 3.60- 3.83 (m, 2 H), 4.69 (br s, 1 H), 5.37- 5.50(m, 1 H), 6.40 (d, J = 8.02 Hz, 1 H), 6.90 (td, J = 8.59, 3.44 Hz, 1 H),7.06 (dd, J = 9.16, 3.44 Hz, 1 H), 7.12 (dd, J = 9.17, 4.58 Hz, 1 H),8.03 (s, 1 H), 8.59 (d, J = 8.02 Hz, 1 H), 8.74 (d, J = 5.16 Hz, 1 H),9.31 (br d, J = 5.16 Hz, 1 H) 58

371.2 0.99 (t, J = 7.45 Hz, 3 H), 1.48 (d, J = 6.87 Hz, 3 H), 1.87-2.00(m, 1 H), 2.42-2.49 (m, 1 H), 3.65-3.80 (m, 2 H), 4.45-4.54 (m, 1 H),5.13-5.24 (m, 1 H), 6.42 (d, J = 7.45 Hz, 1 H), 7.59 (dd, J = 8.59, 2.86Hz, 1 H), 7.92 (d, J = 2.86 Hz, 1 H), 8.03 (s, 1 H), 8.60 (d, J = 7.45Hz, 1 H), 8.75 (d, J = 4.58 Hz, 1 H), 9.07 (br d, J = 6.30 Hz, 1 H) 59

371.2 9.11 (dd, J = 6.59, 2.58 Hz, 1 H), 8.73 (d, J = 5.16 Hz, 1 H),8.60 (d, J = 8.02 Hz, 1 H), 8.04 (s, 1 H), 7.95-7.98 (m, 1 H), 7.62 (dd,J = 8.88, 3.15 Hz, 1 H), 6.41 (d, J = 8.02 Hz, 1 H), 5.22-5.29 (m, 1 H),4.73-4.84 (m, 1 H), 3.74-3.79 (m, 2 H), 3.67 (ddd, J = 13.17, 6.87, 4.58Hz, 2 H), 1.63 (d, J = 6.30 Hz, 3 H), 1.48 (d, J = 6.87 Hz, 3 H) 60

371.2 9.67 (d, J = 8.02 Hz, 1 H), 8.81 (d, J = 6.87 Hz, 1 H), 8.59 (d, J= 7.45 Hz, 1 H), 8.05 (s, 1 H), 8.02 (d, J = 2.86 Hz, 1 H), 7.68 (dd, J= 8.59, 2.86 Hz, 1 H), 6.37 (d, J = 7.45 Hz, 1 H), 5.34-5.42 (m, 1 H),5.02-5.12 (m, 1 H), 3.97 (ddd, J = 13.32, 9.02, 4.01 Hz, 1 H), 3.13 (td,J = 11.74, 1.15 Hz, 1 H), 1.50 (d, J = 7.45 Hz, 3 H), 1.46 (d, J = 6.30Hz, 3 H) 61

399.2 9.33-9.81 (m, 1 H), 8.98-9.17 (m, 1 H), 8.60-8.66 (m, 1 H),8.03-8.18 (m, 2 H), 7.18-7.28 (m, 1 H), 7.01-7.12 (m, 2 H), 6.59-6.66(m, 1 H), 6.28-6.34 (m, 1 H), 6.07 (dd, J = 7.16, 1.43 Hz, 1 H), 4.88(dt, J = 5.87, 3.94 Hz, 1 H), 4.43-4.51 (m, 1 H), 3.83-3.98 (m, 1 H),3.51-3.57 (m, 1 H), 3.13-3.20 (m, 1 H), 2.61 (dd, J = 11.46, 4.58 Hz, 3H), 1.49 (d, J = 6.30 Hz, 2 H), 1.08 (d, J = 6.30 Hz, 1 H) 62

413.2 9.35-9.81 (m, 1 H), 8.92-9.03 (m, 1 H), 8.59-8.65 (m, 1 H),8.04-8.12 (m, 1 H), 7.05-7.15 (m, 3 H), 6.70-6.79 (m, 1 H), 6.35-6.69(m, 1 H), 4.53-4.99 (m, 1 H), 3.91-4.01 (m, 1 H), 3.45-3.50 (m, 1 H),3.44-3.49 (m, 1 H), 3.11-3.19 (m, 1 H), 2.93-3.09 (m, 3 H), 2.83-2.88(m, 3 H), 1.45 (d, J = 5.73 Hz, 2 H), 1.00 (d, J = 6.30 Hz, 1 H)

Biologic Assays

Creation of CD74-ROS1 and EML4-ALK Ba/F3 Stable Cell Lines and CellProliferation Assays.

The CD74-ROS1 wild-type gene and EML4-ALK wild-type gene (variant 1)were synthesized at GenScript and cloned into pCDH-CMV-MCS-EF1-Puroplasmid (System Biosciences, Inc). Ba/F3-CD74-ROS1 and Ba/F3-EML4-ALKwild type cell lines were generated by infecting Ba/F3 cells withlentivirus containing CD74-ROS1 wide-type and EML4-ALK wild type. Stablecell lines were selected by puromycin treatment, followed by IL-3withdrawal. 3000 cells were seeded in 384 well white plate overnightbefore compound treatment. Cell proliferation was measured usingCellTiter-Glo luciferase-based ATP detection assay (Promega) followingthe manufactures's protocol after 72 hours of various concentration ofcompound incubation. IC₅₀ determinations were performed using GraphPadPrism software (GraphPad, Inc., San Diego, Calif.).

Cell Proliferation Assays.

Colorectal cell lines KM 12 (harboring endogenous TPM3-TRKA fusion gene)cells were cultured in DMEM medium, supplemented with 10% fetal bovineserum and 100 U/mL of penicillin/streptomycin. 5000 cells were seeded in384 well white plate for 24 hours before compounds treatment. Cellproliferation was measured using CellTiter-Glo luciferase-based ATPdetection assay (Promega) following the manufactures's protocol after 72hours incubation. IC₅₀ determinations were performed using GraphPadPrism software (GraphPad, Inc., San Diego, Calif.). Alternatively,essential thrombocythemia cell line SET-2 cells (harboring endogenousJAK2 V618F point mutation) or T cell lymphoma Karpas-299 cell line(harboring endogenous NPM-ALK fusion gene) were cultured in RPMI medium,supplemented with 10% fetal bovine serum and 100 U/mL ofpenicillin/streptomycin. 5000 cells were seeded in 384 well white platefor 24 hours before compounds treatment. Cell proliferation was measuredusing CellTiter-Glo luciferase-based ATP detection assay (Promega)following the manufactures's protocol after 72 hours incubation. IC₅₀determinations were performed using GraphPad Prism software (GraphPad,Inc., San Diego, Calif.).

Cell Proliferation IC₅₀ (μM) Com- CD74-ROS1 EML4-ALK Karpas pound Ba/F3Ba/F3 299 KM12 SET2 1 0.0002 0.0134 0.0167 0.0002 0.0676 2 0.0007 0.6810.354 0.006 0.956 3 0.0002 0.138 0.083 0.0003 0.263 4 0.0002 0.892 1.3680.0003 1.371 5 0.0279 2.032 0.794 0.0165 0.852 6 0.0028 0.1165 0.0650.0005 0.164 7 0.0226 0.715 0.438 0.0168 0.190 8 0.0347 2.129 1.5020.017 0.406 9 0.0002 0.0002 0.073 0.0004 0.093 10 0.0002 0.0963 0.0800.0014 0.057 11 0.0189 2.429 0.59 0.002 0.187 12 0.130 5.095 2.27 0.0421.96 13 0.112 1.482 3.215 0.069 4.033 14 0.300 >10 >10 0.180 3.777 151.00 >10 >10 0.160 4.789 16 0.112 1.908 0.470 0.0004 0.665 17 0.0032.687 0.297 0.0002 0.005 18 0.0002 0.0284 0.0247 0.0002 0.0986 19 0.00050.406 0.193 0.0006 0.294 20 0.0002 0.151 0.144 0.003 0.404 21 0.04526.786 8.033 0.003 1.131 22 1.00 >10 0.352 0.022 0.854 23 0.0051 0.459N/A 0.0013 0.236 24 0.008 0.475 0.264 0.005 1.325 25 NA 0.0885 0.1660.0061 0.134 26 0.0002 0.162 27 0.053 3.0 28 0.229 4.5 29 0.0055 0.49230 0.003 0.671 31 >10 >10 32 0.192 5.8 33 8.0 >10 34 0.0059 0.899 350.00027 1.07 36 0.0078 1.24 37 0.30 5.0 38 0.0071 39 3.0 0.315 40 3.00.042 41 0.150 0.003 0.0785 42 0.080 0.0002 0.030 43 0.080 0.001 0.04444 3.00 0.056 1.80 45 >10 0.0004 0.206 46 2.00 0.011 0.400 47 0.5040.006 0.127 48 5.0 >10 >10 49 >10 2.41 50 3.0 0.178 51 >10 0.0518 521.482 0.0087 0.768 53 3.0 0.0373 0.505 54 >10 0.464 >10 55 0.709 0.02350.300 56 >10 0.527 57 0.665 0.070 0.132 58 0.031 0.0002 0.174 59 2.00.0055 0.402 60 0.218 0.00035 0.0303 61 8.0 0.0737 1.07 62 3.0 0.1123.569

1-61. (canceled)
 62. A method of treating cancer, pain, neurologicaldiseases, autoimmune diseases, or inflammation comprising administeringto a subject in need of such treatment an effective amount of a compoundof the formula I

wherein M is CR^(4a) or N; M¹ is CR⁵ or N; X¹ and X² are independentlyS, S(O), S(O)₂, O or N(R⁹); R¹ is H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl; each R³ is independently H, deuterium,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl isindependently optionally substituted by deuterium, halogen, —OH, —CN,—OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆alkyl), —N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆alkyl), —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl: R² and R⁶ taken together with the atomsto which they are attached form a 5- to 7-membered heterocycloalkyl: R⁴,R^(4a) and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆alkyl, —OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —C₃;each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or heteroaryl; each R⁹ is independently H,deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or monocyclic orbicyclic heteroaryl; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or monocyclic or bicyclic heteroaryl isindependently optionally substituted by deuterium, halogen, C₁-C₆ alkyl,C₁-C₆ haloalkyl or —OR⁷; Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, and Z⁷ are eachindependently N, NH, C, or C(R¹⁰), wherein each R¹⁰, when present, isindependently H, deuterium, halogen, C₁-C₆ alkyl, —OC₁-C₆ alkyl, —OH,—NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl), —NH(heteroaryl), —CN, or —CF₃, andn is 1 or 2; provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, andZ⁷ is N or NH; and provided that at least one R¹, R² or R³ is not H; ora pharmaceutically acceptable salt thereof. 63-67. (canceled)
 68. Themethod of claim 62, wherein the compound has the formula Ia

wherein M is CR^(4a) or N; X¹ and X² are independently S, S(O), S(O)₂, Oor N(R⁹); R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein each hydrogenatom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl andC₆-C₁₀ aryl is independently optionally substituted by deuterium,halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂,—NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂,—NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆alkyl), —NHS(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl), —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl),—NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl; each R³ is independently H, deuterium, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl; R² and R⁶ taken together with the atomsto which they are attached form a 5- to 7-membered heterocycloalkyl; R⁴,R^(4a) and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆alkyl, —OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or—CF₃; each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or heteroaryl; each R⁹ is independently H,deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or monocyclic orbicyclic heteroaryl; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or monocyclic or bicyclic heteroaryl isindependently optionally substituted by deuterium, halogen, C₁-C₆ alkyl,C₁-C₆ haloalkyl or —OR⁷; and Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, and Z⁷ are eachindependently N, NH, C, or C(R¹⁰), wherein each R¹⁰ is independently H,deuterium, halogen, C₁-C₆ alkyl, —OC₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆alkyl), —NH(phenyl), —NH(heteroaryl), —CN, or —CF₃, provided that atleast one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, and Z⁷ is N or NH.
 69. The methodof claim 62, wherein Z¹, Z⁴ and Z⁷ are independently N, Z⁵ is C, and Z²,Z³, and Z⁶ are independently CH.
 70. The method of claim 62, wherein X¹is N(R⁹).
 71. The method of claim 62, wherein R⁹ is H.
 72. The method ofclaim 62, wherein X² is O.
 73. The method of claim 62, wherein R³ is H.74. The method of claim 62, wherein R³ is C₁-C₆ alkyl; wherein eachhydrogen atom in C₁-C₆ alkyl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl.
 75. The method of claim 62, wherein the compound hasthe formula II

wherein M is CH or N; X¹ and X² are independently S, S(O), S(O)₂, O orN(R⁹); R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein each hydrogenatom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl andC₆-C₁₀ aryl is independently optionally substituted by deuterium,halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂,—NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂,—NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆alkyl), —NHS(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl), —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl),—NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, —C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl; R² and R⁶ taken together with the atoms to which theyare attached form a 5- to 7-membered heterocycloalkyl; R⁴ and R⁵ areeach independently H, fluoro, chloro, bromo, C₁-C₆ alkyl, —OH, —CN,—OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃; each R⁷ and R⁸is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or heteroaryl; and each R⁹ is independently H, deuterium, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or monocyclic or bicyclic heteroaryl;wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, ormonocyclic or bicyclic heteroaryl is independently optionallysubstituted by deuterium, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷.76. The method of claim 62, wherein the compound has the formula III

wherein M is CH or N; X¹ and X² are independently S, S(O), S(O)₂, O orN(R⁹); R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein each hydrogenatom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl andC₆-C₁₀ aryl is independently optionally substituted by deuterium,halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂,—NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂,—NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆alkyl), —NHS(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl), —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl),—NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl; R² and R⁶ taken together with the atoms to which theyare attached form a 5- to 7-membered heterocycloalkyl; R⁴ and R⁵ areeach independently H, fluoro, chloro, bromo, C₁-C₆ alkyl, —OH, —CN,—OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃; each R⁷ and R⁸is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or heteroaryl; and each R⁹ is independently H, deuterium, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or monocyclic or bicyclic heteroaryl;wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, ormonocyclic or bicyclic heteroaryl is independently optionallysubstituted by deuterium, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷.77. The method of claim 62, wherein R⁵ is —H.
 78. The method of claim62, wherein R⁴ is fluoro.
 79. The method of claim 62, wherein thecompound is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.
 80. The method of claim62, wherein the compound has the formula XI, formula XII or formula XIII

wherein M is CH or N; X¹ and X² are independently S, S(O), S(O)₂, O orN(R⁹); R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein each hydrogenatom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl andC₆-C₁₀ aryl is independently optionally substituted by deuterium,halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂,—NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂,—NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆alkyl), —NHS(O)₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl), —NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl),—NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl; R² and R⁶ taken together with the atoms to which theyare attached form a 5- to 7-membered heterocycloalkyl; R⁴ and R⁵ areeach independently H, fluoro, chloro, bromo, C₁-C₆ alkyl, —OH, —CN,—OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃; each R⁷ and R⁸is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or heteroaryl; and each R⁹ is independently H, deuterium, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or monocyclic or bicyclic heteroaryl;wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, ormonocyclic or bicyclic heteroaryl is independently optionallysubstituted by deuterium, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or —OR⁷;or a pharmaceutically acceptable salt thereof.
 81. The method of claim80, wherein M is CH.
 82. The method of claim 81, wherein R⁵ is H. 83.The method of claim 82, wherein X¹ is NH.
 84. The method of claim 83,wherein X² is O.
 85. The method of claim 84, wherein R¹ is C₁-C₆ alkyl,wherein each hydrogen atom in C₁-C₆ alkyl is independently optionallysubstituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂,—NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl.
 86. A method of treating cancer, pain, neurologicaldiseases, autoimmune diseases, or inflammation comprising administeringto a subject in need of such treatment an effective amount of apharmaceutical composition comprising a compound of the formula I

wherein M is CR⁴a or N; M¹ is CR⁵ or N; X¹ and X² are independently S,S(O), S(O)₂, O or N(R⁹); R¹ is H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸;wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independently optionally substitutedby deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl; each R³ is independently H, deuterium,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl isindependently optionally substituted by deuterium, halogen, —OH, —CN,—OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆alkyl), —N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆alkyl), —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H,—C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl; R² and R⁶ taken together with the atomsto which they are attached form a 5- to 7-membered heterocycloalkyl; R⁴,R^(4a) and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆alkyl, —OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or—CF₃; each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or heteroaryl; each R⁹ is independently H,deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or monocyclic orbicyclic heteroaryl; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or monocyclic or bicyclic heteroaryl isindependently optionally substituted by deuterium, halogen, C₁-C₆ alkyl,C₁-C₆ haloalkyl or —OR⁷; Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, and Z⁷ are eachindependently N, NH, C, or C(R¹⁰), wherein each R¹⁰, when present, isindependently H, deuterium, halogen, C₁-C₆ alkyl, —OC₁-C₆ alkyl, —OH,—NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl), —NH(heteroaryl), —CN, or —CF₃, andn is 1 or 2; provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, andZ⁷ is N or NH; and provided that at least one R¹, R² or R³ is not H; ora pharmaceutically acceptable salt thereof, and at least one diluent,carrier or excipient.